JP2006522812A - Heterocyclic MCHR1 antagonist - Google Patents

Abstract

The present invention relates to novel heterocycles that are antagonists of melamine-concentrating hormone receptor 1 (MCHR1), also referred to as 11CBy, pharmaceutical compositions containing it, methods for their preparation and their use in pharmaceuticals. The compounds of the present invention have the formula (I)

Description

  The present invention relates to novel heterocycles that are antagonists of melanin-concentrating hormone receptor 1 (MCHR1), also referred to as 11CBy, pharmaceutical compositions containing it, methods for their preparation, and their use in therapy.

  Obesity is a medical condition that has reached epidemic scale among humans in many countries around the world. This is a condition that accompanies or induces another disease or condition or that disrupts the activity and lifestyle of life. Obesity is recognized as a serious risk factor for other diseases and conditions such as diabetes, hypertension and arteriosclerosis. It is also known that heavy weight due to obesity can strain joints such as knee joints, resulting in arthritis, pain and ankylosis.

  Overeating and obesity can be such a problem in the normal population, so many individuals are now interested in weight loss, weight loss and / or maintaining a healthy weight and desirable lifestyle.

WO01 / 21577 (Takeda) relates to a compound of the following formula or a salt thereof, which is an antagonist of melanin-concentrating hormone. Such compounds have been suggested to be useful for preventing or treating obesity.

[In the formula, Ar ¹ is a cyclic group which may have a substituent, X is a spacer having a main chain of 1 to 6 atoms, and Y is a bond or 1 to 6 And Ar is a monocyclic aromatic ring which may be condensed with a 4- to 8-membered non-aromatic ring or may further have a substituent, R ¹ and R ² are independently hydrogen or an optionally substituted carbocyclic group, and R ¹ and R ² together with the adjacent nitrogen atom may contain an optionally substituted nitrogen R ² may form a spiro ring with Ar, or R ² together with the adjacent nitrogen atom may form a nitrogen-existing heterocyclic ring that may have a substituent. May be]

WO01 / 82925A1 (Takeda) relates to a compound of the following formula or a salt thereof.

[Wherein Ar ¹ is an optionally substituted cyclic group;
X and Y are the same or different spacers having 1 to 6 atoms in the main chain;
Ar is an optionally substituted fused polycyclic aromatic ring,
R ¹ and R ² are the same or different and are a hydrogen atom or an optionally substituted hydrocarbon group, or R ¹ and R ² together with the adjacent nitrogen atom may contain an optionally substituted nitrogen A heterocycle may be formed, and R ² together with the adjacent nitrogen atom and Y may form an optionally substituted nitrogen-containing heterocycle, or R ² may be an adjacent nitrogen atom, Y And Ar may form an optionally substituted nitrogen-containing heterocyclic ring or a salt thereof]

WO01 / 21577A2 (Takeda) relates to an aromatic compound of the following formula or a salt thereof, which is useful as a drug for preventing or treating obesity.

P32897WO1 (GlaxoSmithKline) relates to a compound of the following formula or a salt thereof, a process for its preparation, a pharmaceutical composition containing them and its use in medicine.

Wherein M is a group selected from O, S, CO, NH or CH ₂ , L is a 2 or 3 membered alkylene chain, and the chain -ML is methyl, ethyl, hydroxy Or may be substituted by one or more groups selected from alkoxy, or the chain may contain a -C = C- double bond, and R ₁ and R ₂ are each independently hydrogen, C ₁ -C ₆ represents a linear or branched alkyl, these are optionally substituted with one or more C ₁ -C ₆ phenyl or C ₃ optionally substituted by an alkyl group -C ₆ cycloalkyl Or R ₁ and R ₂ together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ring or a 7-10 membered bridged heterocyclic ring, which is a phenyl group or 4 _C 1 _{~C 3} alkyl of up to individual Or may be substituted by a group or R ₁ or R _2, either may be crosslinked to the group L, by crosslinking as part of a substituent X is located in the phenyl ring, form a cyclic group Group X may be bonded to group L to form a cyclic group which may contain additional oxygen, sulfur or nitrogen atoms, or alternatively or in addition to these. May be one or more substituents X selected from hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, halogen, C ₂ -C ₃ alkenyl, benzyl, CR _a NOR _b , Where R _a and R _b are independently hydrogen or methyl, methoxy-methyl, methoxymethoxy or methoxyethoxy, QY is a bicyclic fused heterocycle, where Y is a bicyclic fused One ring of a heterocyclic group This is through a nitrogen atom therein, and cross-linked to the phenyl ring is substituted by a group ZR ₃ at the second ring Q, Z is a bond or NH, NCH 3, _O, S Or a group selected from CH ₂ , wherein R ₃ is a group selected from aryl, 2-alkenyl, cycloalkyl or 2-cycloalkenyl, and this R ₃ group is one or more C _1- C ₃ alkyl, halo, amino, alkylamino, dialkylamino, hydroxy, C ₁ -C ₃ alkoxy, cyano, optionally substituted by trifluoromethyl or methylthio group]

P32897WO2 (GlaxoSmithKline) provides a formulation, a preparation method and a method for administration to a mammal with respect to a compound represented by the following formula, a pharmaceutically acceptable salt or solvate thereof.

Aventis WO03 / 015769A1 relates to aminoalkyl-substituted aromatic compounds of the formula: The said compound can be used appropriately as an appetite lowering agent.

  In particular, melanin-concentrating hormone (“MCH”) is derived from the hypothalamus and has an appetite promoting action (see, for example, Nature, Vol. 396, p. 670, (1998)). There is an increasing need to develop melanin-concentrating hormone antagonists useful in treating obesity and other concomitant or related diseases and conditions.

  Thus, the inventors have described Nature, Vol. 400, p. A new group of heterocycles has been found that exhibit activity profiles useful as antagonists of the melanin-concentrating hormone receptor (MCHR1) disclosed in 261-265 (1999).

The present invention provides a compound of formula (I), a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

[Where:

Is at least selected from the group consisting of C ₁ -C ₆ linear or branched alkyl, alkenyl, halo, amino, alkylamino, dialkylamino, hydroxy, C ₁ -C ₆ alkoxy, cyano, nitro and alkylthio groups An aryl or heteroaryl optionally substituted with 1 to 4 substituents,
The dotted line connecting Q ² and Q ³ represents an optional bond,
q, r, s and t are each independently 0 or 1,
When q is 1, the bond between Q ² and Q ³ is a double bond,
Q ¹ and Q ³ are each independently C or N;
when q is 0, Q ² is N, S or O;
when q is 1, Q ² is C or N; when q is 1 and Q ² is N, s is 0;
When Q ² is S or O, s is 0;
When Q ¹ is N, r is 0;
When Q ³ is N, t is 0;
R ³ is selected from the group consisting of hydrogen, amino, C ₁ -C ₆ linear or branched alkyl, C ₃ -C ₆ cycloalkyl and C ₁ -C ₃ alkylthio;
When Q ¹ or Q ³ is C, each corresponding R ⁴ is independently hydrogen, C ₁ -C ₆ linear or branched alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, Selected from the group consisting of amino, alkylamino, dialkylamino, hydroxy, cyano, alkylthio and halo;
When q is 1 and Q ² is C or q is 0 and Q ² is N, R ⁵ is hydrogen, C ₁ -C ₆ straight or branched alkyl, C _3- C _{6 cycloalkyl,} C 1 -C ₆ alkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, selected from alkylthio and halo,
Ar is at least one selected from the group consisting of C ₁ -C ₆ straight or branched alkyl, alkenyl, halo, amino, alkylamino, dialkylamino, hydroxy, C ₁ -C ₆ alkoxy, cyano and alkylthio groups A fused bicyclic ring optionally substituted with 1 to 4 species substituents,
Y is a bond or an optionally substituted C ₁ -C ₆ alkylene;
(I) R ¹ and R ² are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ straight or branched chain alkyl, C ₃ -C ₆ cycloalkyl and a 5 or 6 membered heterocycle. said alkyl, said cycloalkyl and said heterocycle, _phenyl, C 1 -C ₃ alkyl, _amino, C 1 -C _{6 alkylamino,} C 1 -C ₆ dialkylamino, hydroxy, oxo (i.e., = O), Optionally substituted with 1 to 4 at least one substituent selected from the group consisting of alkoxy, or halo, or (ii) R ¹ and R ² are each selected from aryl and N, O, and S Selected from the group consisting of 5-membered or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms, wherein said aryl and said hete Aryl, _halo, C 1 -C ₆ straight or branched chain _alkyl, C 3 -C _{6 cycloalkyl,} C 1 -C _{6 alkenyl,} C 3 -C ₆ cycloalkenyl, _hydroxy, C 1 -C ₆ alkoxy, _amino, C 1 -C _{6 alkylamino,} C 1 -C _{6 dialkylamino,} C 1 -C _{6 alkylthio,} C 1 -C ₆ alkylsulfinyl substituents selected from the group consisting of Le and phenyl, 2 or 3 in Or (iii) R ¹ and R ² together with the nitrogen atom to which they are attached form a 4-8 membered or 7-11 membered bicyclic heterocycle; The 4- to 8-membered heterocyclic ring and the 7- to 11-membered bicyclic heterocyclic ring each contain 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, and the heterocyclic ring Also Any of the bicyclic heterocycles is phenyl, C ₁ -C ₃ alkyl, hydroxy, C ₁ -C ₃ alkoxy, oxo (ie, ═O), amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ may be substituted with 1 to 4 substituents selected from the group consisting of ₆ alkylalkyl or halo, or (iv) R ² is substituted with the adjacent nitrogen atom and Y May form a nitrogen-containing heterocyclic ring that may be substituted, or R ² may form an optionally substituted nitrogen-containing heterocyclic ring or a salt thereof together with the adjacent nitrogen atom, Y and Ar, the heterocyclic ring, _phenyl, C 1 -C ₃ alkyl, _hydroxy, C 1 -C ₃ alkoxy, oxo (i.e., = O), _amino, C 1 -C _{6 alkylamino,} C 1 -C ₆ dialkyl It may be substituted with four at least one one substituent selected from arylamino the group consisting of halo

  In another aspect of the present invention, there is provided a pharmaceutical composition for use in the treatment, prevention or both of one or more conditions or indications described herein, comprising a compound of formula (I) Or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof and a pharmaceutically acceptable carrier or excipient. Further, a method of treatment comprising administering to a mammal such as a human a compound of formula (I) as defined above, as well as obesity, diabetes, depression and / or anxiety in a mammal (eg human) There is provided the use of said compound in the manufacture of a medicament for treating a condition.

  In another embodiment of the invention, a process for the preparation of a compound of formula (I) is provided.

  As used herein, “a compound of the invention” or “a compound of formula (I)” refers to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof (eg , Prodrug).

  As used herein, unless otherwise stated, the terms “alkyl” and “alkylene” relate to straight or branched hydrocarbon chains containing from 1 to 6 carbon atoms. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, t-butyl and hexyl. . Examples of “alkylene” as used herein include, but are not limited to, methylene, ethylene, propylene, butylene, and isobutylene. “Alkyl” further includes substituted alkyl. Further, “alkylene” includes substituted alkylene. Alkyl and alkylene groups may be optionally substituted with at least one substituent selected from the group consisting of hydroxy, alkoxy, halo, amino, alkylamino, dialkylamino, thio, oxo, aryl and cyano. Particularly preferred are halo, alkoxy and hydroxy.

  As used herein, unless otherwise stated, the term “cycloalkyl” has 3 to 8 carbon atoms (unless otherwise stated) and has a carbon-carbon double bond. Does not relate to non-aromatic carbocycles. “Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. “Cycloalkyl” further includes substituted cycloalkyl. Cycloalkyl may be optionally substituted with at least one substituent selected from the group consisting of hydroxy, cyano, halo, alkoxy, amino, alkylamino, dialkylamino and alkyl. Halo, hydroxy and alkoxy are preferred.

  As used herein, unless otherwise stated, the term “alkenyl” refers to a straight chain containing 2 to 8 carbon atoms and at least 1 to 3 carbon-carbon double bonds, or Relates to branched hydrocarbon chains. Examples of “alkenyl” as used herein include, but are not limited to, ethenyl and propenyl. “Alkenyl” further includes substituted alkenyl. The alkenyl group may be optionally substituted with at least one substituent selected from the group consisting of alkyl, amino, alkylamino, dialkylamino, halo, hydroxy, alkoxy and cyano. Halo, hydroxy and alkoxy are preferred.

As used herein, unless otherwise stated, the term “cycloalkenyl” refers to 3 to 8 carbon atoms (unless otherwise stated) and up to 3 carbon-carbon double bonds. It has a non-aromatic carbocyclic ring. “Cycloalkenyl” includes, for example, cyclobutenyl, cyclopentenyl and cyclohexenyl. “Cycloalkenyl” further includes substituted cycloalkenyl. This ring is cyano, halo, hydroxy, —NH ₂ , —N ₃ , —CN, —O—C ₁ -C ₃ alkyl, —NH (C ₁ -C ₃ alkyl), —N (C ₁ -C _3). Alkyl) ₂ and optionally substituted with at least one substituent selected from the group consisting of -C ₁ -C ₃ alkyl (including haloalkyl).

  As used herein, the term “halo” or “halogen” relates to fluorine, chlorine, bromine and iodine. Of these, chlorine (or “chloro”) and fluorine (or “fluoro”) are preferred.

  Unless otherwise stated, the term “aryl” (and also “aromatic”) refers to monocyclic carbocyclic groups and fused bicyclic rings having from 6 to 12 carbon atoms and having at least one aromatic ring. Relates to a carbocyclic group of formula Specific examples of aryl groups include, but are not limited to, phenyl and naphthyl. “Aryl” further includes substituted aryl, especially substituted phenyl. Aryl rings are halo, alkyl (including haloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy, amino, hydroxy, hydroxyalkyl, aminoalkyl, carboxy, carboxamide, sulfonamide, heteroaryl (abbreviated “Het”), It may be optionally substituted with at least one substituent selected from the group consisting of amidine, cyano, nitro and azide. Preferred aryl groups according to the present invention include, but are not limited to, phenyl and substituted phenyl. Preferred substituted phenyl is phenyl containing one or more halo groups, especially chloro and fluoro groups.

  The terms “heterocycle” and “heterocyclic” relate to a ring system consisting of C and at least one other atom selected from the group consisting of N, O and S. The heterocycle may or may not be heteroaromatic as defined below. In other words, heteroaromatics are heterocycles, but not all heterocycles are heteroaromatics.

  The terms “heteroaryl” and “heteroaromatic” relate to monocyclic or bicyclic aromatic ring systems consisting of C and at least one other atom selected from the group consisting of N, O and S.

  The term “membered” (and variations thereof, eg “membered”) with respect to heterocycles, heteroaryls and aryl groups refers to all atoms of the carbon and heteroatoms (N, O and / or S) forming the ring. About. Thus, an example of a 6-membered heterocycle is piperidine, an example of a 6-membered heteroaryl ring is pyridine, and an example of a 6-membered aryl ring is benzene.

  As used herein, the term “sometimes” means that an event that is described later may or may not occur, when an event occurs and when an event does not occur Both are included.

The formula (I) of the present invention will be described in detail later.

_Is, C 1 -C ₆ straight or branched chain alkyl, alkenyl, halo, amino, alkylamino, dialkylamino, _hydroxy, C 1 -C ₆ alkoxy, cyano, at least is selected from the group consisting of nitro and alkylthio groups Aryl or heteroaryl optionally substituted 1 to 4 times with one substituent. Of these substituted groups, _halo, and C 1 -C ₃ alkyl and _C 1 -C ₃ alkoxy preferred. Fluoro, chloro and methoxy are particularly preferred. In a preferred embodiment, the

Is substituted with a halo group, q is 0, Q ¹ is carbon, Q ² is sulfur, and R ⁴ is hydrogen or halo. For example,

Is 4-chlorophenyl and R ³ and R ⁴ are each hydrogen.

Wherein the dotted line connecting the, Q ² and Q ³ are, Q ² and bond with Q ³ represents an optional (optional) coupled as linked by a double bond, q, r, s and t are each Independently, 0 or 1.

In the formula (I), q is 0 or 1. When q is 1, the bond between Q ² and Q ^{3 in} formula (I) is a double bond. when q is 0, ^{Q 3} group is not present. When q is 0, Q ² is N, S or O. When q is 1, Q ² is C or N. When q is 1 and Q ² is N, s is 0 and there is no R ⁵ substituent.

Q ¹ and Q ³ are each independently carbon (C) or nitrogen (N). In one embodiment, Q ¹ , Q ² and Q ³ are each carbon and q, r, s and t are 1. In other embodiments, Q ¹ is carbon, Q ² is sulfur, q and s are 0, and r is 1.

In the formula, r and t are each independently 0 or 1. When r and t are each independently 0, there is no R ⁴ substituent. When r and t are each independently 1, Q ¹ and Q ³ are each independently linked by the group R ⁴ . Each R ⁴ is the same or different and is hydrogen, C ₁ -C ₆ linear or branched alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, amino, alkylamino, dialkylamino, Independently selected from the group consisting of hydroxy, cyano, alkylthio and halo.

In the formula (I), s is 0 or 1. When Q ² is S or O, s is 0 and there is no R ⁵ group. When Q ² is C, s is 1 and R ⁵ is hydrogen, C ₁ -C ₆ straight or branched alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, amino, Selected from the group consisting of alkylamino, dialkylamino, hydroxy, cyano, alkylthio and halo. When Q ² is C, preferably R ⁵ is hydrogen or C ₁ -C ₃ alkyl, more preferably R ⁵ is hydrogen or methyl.

In formula (I), R ³ is selected from the group consisting of hydrogen, amino, C ₁ -C ₆ straight or branched chain alkyl and C ₃ -C ₆ cycloalkyl. Preferably R ³ is hydrogen or C ₁ -C ₃ alkyl, more preferably R ³ is hydrogen or methyl.

When either Q ¹ and Q ³ or both are C, R ⁴ is hydrogen, C ₁ -C ₆ linear or branched alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy , Amino, alkylamino, dialkylamino, hydroxy, cyano, alkylthio and halo. Preferably, when either Q ¹ and Q ³ or both are C, R ⁴ is hydrogen or C ₁ -C ₃ alkyl, more preferably R ⁴ is hydrogen or methyl.

When Q ² is N and s is 1, R ⁵ is hydrogen, C ₁ -C ₆ straight or branched alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, amino, Selected from the group consisting of alkylamino, dialkylamino, hydroxy, cyano, alkylthio and halo. When Q ² is N and s is 1, preferably R ⁵ is hydrogen or C ₁ -C ₃ alkyl, and more preferably R ⁵ is hydrogen or methyl.

Wherein (I), Ar _is, C 1 -C ₆ straight or branched chain alkyl, alkenyl, halo, amino, alkylamino, dialkylamino, _hydroxy, C 1 -C ₆ alkoxy, the group consisting of cyano and alkylthio groups It is an optionally substituted fused bicyclic ring having 9 to 14 members, which may be substituted 1 to 4 times by at least one substituent selected from That is, Ar is (i) two aromatic rings fused together, (ii) one aromatic ring and one heteroaromatic ring fused together, (iii) fused together Or a fused bicyclic ring having (iv) an aromatic ring fused to a heterocyclic ring or (v) an aromatic ring fused to a carbocyclic ring. Preferably Ar is selected from the group consisting of quinoline, naphthalene, benzimidazole, indole, benzothiophene, benzofuran and benzothiazole. When Ar is a 10-membered bicyclic aromatic or 10-membered bicyclic heteroaromatic ring, preferably Ar is quinoline or naphthalene. When Ar is a 9-membered fused bicyclic heteroaromatic ring, preferably Ar is benzimidazole, indole, benzothiophene, benzofuran or benzothiazole.

In formula (I), Y is a bond or C ₁ -C ₆ alkylene, which may be substituted as defined herein. When Ar is a 10-membered polycyclic aromatic or 10-membered polycyclic heteroaromatic ring, preferably Y is an optionally substituted C ₁ -C ₃ alkylene, most preferably Y is an optionally substituted methylene (—CH ₂ —). When Ar is a 9-membered fused polycyclic heteroaromatic ring, preferably, Y is a bond, an optionally C ₁ -C ₃ alkylene optionally substituted, more preferably, Y is a bond is there.

In (i), R ¹ and R ² in formula (I) are each independently hydrogen, C ₁ -C ₆ linear or branched alkyl, C ₃ -C ₆ cycloalkyl, phenyl and 5 or 6 membered is selected from the group consisting of heterocycle, wherein said alkyl, said cycloalkyl and said heterocycle, _phenyl, C 1 -C ₃ alkyl, _amino, C 1 -C _{6 alkylamino,} C 1 -C ₆ dialkylamino , Hydroxy, oxo, alkoxy and halo may be substituted one to four times with at least one substituent selected from the group consisting of. Preferably, R ¹ and R ² are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ straight or branched alkyl and C ₃ -C ₆ cycloalkyl. Most preferably, R ¹ and R ² are each independently selected from the group consisting of hydrogen, C ₁ -C ₃ alkyl and C ₃ -C ₆ cycloalkyl.

Or (ii), R ¹ and R ² are selected from the group consisting of aryl and 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S; wherein said aryl and said heteroaryl is selected from _halo, C 1 -C ₆ straight or branched chain _alkyl, C 3 -C _{6 cycloalkyl,} C 1 -C _{6 alkenyl,} C 3 -C ₆ cycloalkenyl, hydroxy At least selected from the group consisting of C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfinyl and phenyl It may be substituted with one, two, or three substituents. Preferably, when ^one of R ¹ or R ² is aryl or heteroaryl, the other of the remaining R ¹ or R ² is hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl.

In addition, in (iii), R ¹ and R ² together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ring or a 7-11 membered bicyclic heterocyclic ring. The 4-8 membered heterocycle and / or the 7-11 membered bicyclic heterocycle may comprise 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S. Any heterocyclic ring or bicyclic heterocyclic ring, _phenyl, C 1 -C ₃ alkyl, _hydroxy, C 1 -C ₃ alkoxy, _amino, C 1 -C _{6 alkylamino,} C 1 -C ₆ dialkylamino, oxo And optionally substituted with 1 to 4 at least one substituent selected from the group consisting of halo. In this case, neither group R ¹ or R ² is bound to M or L. Preferably R ¹ and R ^{2 taken} together are a 5-6 membered heterocyclic ring or an 8-11 membered bicyclic ring having 1 or 2 heteroatoms selected from the group consisting of N, O and S Forming a heterocyclic ring, wherein said heterocyclic ring and said bicyclic heterocyclic ring may be optionally substituted up to two times with a substituent selected from the group consisting of oxo and halo.

In addition, in (iv), R ² together with the adjacent nitrogen atom and Y may form an optionally substituted nitrogen-containing heterocycle, or R ² is the adjacent nitrogen atom, Y and Ar In addition, an optionally substituted nitrogen-containing heterocyclic ring or a salt thereof may be formed. The nitrogen-containing heterocycle is phenyl, C ₁ -C ₃ alkyl, hydroxy, C ₁ -C ₃ alkoxy, oxo (ie, ═O), amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino. And optionally substituted with 1 to 4 at least one substituent selected from the group consisting of halo. Preferably, when Y is a C ₁ -C ₆ alkyl group, R ² together with the adjacent nitrogen atom and Y forms a 3-7 membered ring. Most preferably, a 5-7 membered ring occurs. 5- to 7-membered ring include phenyl, one to four _C 1 -C ₃ alkyl, hydroxy, alkoxy, oxo, _amino, C 1 -C _{6 alkylamino,} from the group consisting of C 1 -C ₆ dialkylamino, or halo It may be substituted with at least one selected substituent.

In one embodiment, when Ar is a 10-membered aromatic ring or a 10-membered heteroaromatic ring, the most preferred compound according to the invention is
6- (4-chlorophenyl) -3- {6-[(4-hydroxy-1-piperidinyl) methyl] -2-naphthalenyl} thieno [3,2-d] pyrimidin-4 (3H) -one,
6- (4-chlorophenyl) -3- [6- (pyrrolidin-1-ylmethyl) -2-naphthyl] thieno [3,2-d] pyrimidin-4 (3H) -one,
6- (4-Chlorophenyl) -3- {2-[(4-methylpiperazin-1-yl) methyl] -1-benzothien-5-yl} thieno [3,2-d] pyrimidine-4 (3H)- on,
6- (4-fluorophenyl) -3- [2- (piperidin-1-ylmethyl) quinolin-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one,
6- (4-Chlorophenyl) -3- {2-[(2-methyl-4,5-dihydro-1H-imidazol-1-yl) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidine -4 (3H) -on,
6- (4-Chlorophenyl) -3- {2-[(2,2,6,6-tetramethylpiperidin-1-yl) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidine-4 (3H) -On,
6-phenyl-3- [2- (pyrrolidin-1-ylmethyl) quinolin-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one,
6-Phenyl-3- [2- (pyrrolidin-1-ylmethyl) quinolin-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one.

  In another embodiment, when Ar is a 9 membered heteroaromatic ring, the most preferred compound according to the invention is 6- (4-chlorophenyl) -3- [2- (dimethylamino) -1-methyl-1H- Benzimidazol-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one.

  Certain compounds of formula (I) may exist in stereoisomeric forms (eg, they may contain one or more asymmetric carbon atoms or may exist in cis-trans isomerism). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The invention further covers the individual isomers of the compounds represented by formula (I) as well as mixtures with isomers thereof in which one or more chiral centers are reversed. Certain compounds of formula (I) can also be prepared as regioisomers. The present invention covers both mixtures of regioisomers and individual compounds. Similarly, it will be understood that compounds of formula (I) may exist in tautomeric forms other than those shown in the formula and these are also included within the scope of the present invention. .

It will be understood that the present invention includes all combinations and subsets of the specific groups defined above. Specific compounds of formula (I) include, but are not limited to, those listed in Table 1 and / or those prepared in the examples herein.

  Those skilled in the art will appreciate that the compounds of the present invention can also be utilized in the form of their pharmaceutically acceptable salts or solvates or physiologically functional derivatives (eg, prodrugs). I will. Pharmaceutically acceptable salts of the compounds of formula (I) include the conventional salts derived from pharmaceutically acceptable inorganic or organic acids or bases, as well as quaternary ammonium salts. More specific examples of suitable acid salts include maleic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, Lactic acid, array acid (alicic), tartaric acid, citric acid, palmoic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid (mesylate), Salts such as naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, steric acid, tannic acid and the like are included.

  Other acids such as pharmaceutically unacceptable oxalic acid per se can also help in preparing salts that serve as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N, N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucose. Kamin and procaine salts are included.

  The term “solvate” as used herein refers to a variable stoichiometric complex formed by a solute (compound of formula (I)) and a solvent. For example, the solvent includes water, methanol, ethanol and acetic acid.

As used herein, the term “physiologically functional derivative” refers to (directly) a compound of the invention or an active metabolite thereof when administered to an animal, particularly a mammal such as a human. It relates to any pharmaceutically acceptable derivative of a compound of the invention that can be (or indirectly) provided, for example an ester or amide of a compound of formula (I). For example, Burger's Medicinal Chemistry and Drug Discovery , 5 th Edition, Vol. 1: See Principles and Practice.

Methods for preparing pharmaceutical salts, solvates and physiologically functional derivatives of the compounds of formula (I) are conventional in the art. For example, Burger's Medicinal Chemistry and Drug Discovery , 5 th Edition, Vol. 1: See Principles and Practice.

Following the reaction schemes and / or processes outlined or described herein, the following compounds of formula (I) are conventionally prepared.

As will be apparent to those skilled in the art, in the following methods for preparing compounds of formula (I), certain intermediates are pharmaceutical salts, solvates or physiological functions of the compounds. It may be in the form of a derivative. With respect to the intermediates used in the process for preparing the compound of formula (I), the terms or identifiers have the same meaning as described above for the compound of formula (I). In general, methods for preparing pharmaceutically acceptable salts, solvates or physiologically functional derivatives of intermediates are known, and pharmaceutically acceptable salts, solvates or compounds of formula (I) The method for preparing the physiologically functional derivative is the same and is described below. Unless stated otherwise,

, R ⁵ , R ⁴ , R ³ , R ² , R ¹ , Ar, Y, Q ¹ , Q ² , Q ³ , q, r, s, and t are all of the methods listed herein. The definition is the same as in formula (I).

For example, a compound of formula (I) in which R ⁵ is H is prepared by reacting an aniline of formula (II) with a formamidine ester of formula (III) in which R is C ₁ -C ₄ alkyl. be able to.

Using an amide coupling reagent such as EDCl (hydrochloric acid 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide) in a solvent such as methylene chloride, the corresponding amino acid (IV) and the desired aniline (II) Compounds of formula (I) can also be prepared by amide coupling followed by cyclization in a refluxing carboxylic acid such as formic acid.

Compound of formula (Va):

And group:

Can also be prepared by reacting with a compound capable of introducing, wherein T is a leaving group (eg, chloro, bromo, iodo and triflate (—OSO ₂ CF ₃ ).

  For example, from a compound of formula (Va) using a Suzuki coupling reaction with a boronic acid and a palladium catalyst, or using a Stille coupling reaction with an organostannane reagent and a palladium catalyst, the compound of formula (I ) Can be prepared.

In a solvent such as dichloromethane or 1,2-dichloroethane, in the presence of trimethylaluminum, and the amino ester of formula (III) R is a _C 1 -C ₄ alkyl, is reacted with anilines of Formula (II), A compound of formula (I) can also be prepared by generating a compound of formula (Vb) and cyclizing the compound of formula (Vb).

A compound of formula (I) in which R ³ is hydrogen can also be prepared by reacting a sulfur-containing compound such as (VI) with a reducing agent such as Raney nickel in a solvent such as ethanol.

By reducing the corresponding nitroaromatic (VII) using hydrogen and a catalyst (eg 10% Pd supported on carbon), stannous chloride or sodium nitrite, of formula (II) Compounds can be prepared.

From compound (VIIa) and amine (VIIb), a compound of formula VIIc where Y is CH ₂ can be prepared, where T is a leaving group (eg, Cl, Br, I, mesylate and tosylate) It is.

Alternatively, this type of compound can be prepared by reductive amination of an aldehyde of formula (VIII) with an amine of formula (VIIb) in the presence of a reducing agent such as sodium borohydride.

A compound of formula (VIII) wherein Y is a bond by reacting a compound of formula (IX) (where Y is a bond) with an oxidizing agent such as selenium dioxide in a solvent such as dioxane. Can be prepared.

A compound of formula VIIc can be prepared from compound (VIIa) and amine (VIIb) where T is a leaving group.

A compound of formula (II) can also be prepared from compound (IX) where T is a leaving group and amine (VIIb).

  In the present invention, the compounds of formula (I) are believed to be useful in treating depression, anxiety, obesity and / or diabetes. The compounds of the present invention are MCHR1 antagonists and can be used in treating diseases induced by or caused by melanin-concentrating hormone. The compounds of the invention reduce hunger, suppress appetite, control eating and / or result in satiety.

  The present invention provides methods for treating several conditions or diseases such as obesity, diabetes, depression (eg, major depression and / or bipolar disorder) and / or anxiety. Such treatment comprises the step of administering to a mammal, preferably a human, a therapeutically effective amount of a compound of formula (I), including salts, solvates or physiologically functional derivatives thereof. Such treatment further comprises administering to a mammal, preferably a human, a therapeutically effective amount of a pharmaceutical composition containing a compound of formula (I), including salts, solvates or physiologically functional derivatives thereof. Including the steps of: As used herein, the term “treatment” refers to alleviating a particular condition, removing or reducing one or more symptoms of that condition, delaying or eliminating the progression of that condition, and It relates to preventing or delaying the recurrence of the condition in a previously suffered or diagnosed patient or subject.

  As used herein, a “therapeutically effective amount” refers to the biological or medical nature of a cell culture, tissue, system, animal (including humans) in an administered subject, for example as considered by a researcher or clinician. Means the amount of a compound of formula (I) that is sufficient to elicit a dynamic response.

  The exact therapeutically effective amount of a compound of formula (I) is, but is not limited to, the age and weight of the subject being treated, the precise disorder requiring treatment and its severity, the nature of the formulation and the route of administration. Depending on several factors, including, ultimately, at the discretion of the attending physician or veterinarian. Treatment of a compound of formula (I) usually in the range of about 0.1 to about 200 mg / kg body weight of recipient (animal) per day, more usually in the range of about 1 to about 100 mg / kg body weight per day To administer. In general, an acceptable daily dose may be from about 0.1 to about 5000 mg / day, preferably from about 0.1 to about 2000 mg / day. The unit dose is usually administered once or more than once, preferably about 1 to about 4 times per day.

  Administration of the compounds of the invention to animals, particularly mammals such as humans, may be oral (including sublingual), parenteral, nasal, rectal or transdermal administration. Preferably oral administration is used.

  For use in therapy, a therapeutically effective amount of the compound of formula (I) can be administered as the raw chemical, but usually it is present as the active ingredient of a pharmaceutical composition or formulation. Accordingly, the present invention further provides a pharmaceutical composition containing a compound of formula (I). The pharmaceutical composition further contains one or more pharmaceutically acceptable carriers, diluents and / or excipients. One or more carriers, one or more diluents and / or one or more excipients are acceptable in the sense that they are compatible with the other ingredients of the formulation and not harmful to the recipient thereof. It must be possible.

  In another aspect of the invention, a method for preparing a pharmaceutical formulation is provided, which comprises a compound of formula (I) and one or more pharmaceutically acceptable carriers, diluents and / or excipients. Mixing with the agent.

  The pharmaceutical formulation can also be provided in unit dosage forms containing a defined amount of active ingredient per unit dosage. Such a unit may contain a compound of formula (I) in a therapeutically effective dose, or when a plurality of unit dosage forms are administered at a given time, to a desired therapeutically effective dose. It may contain a portion of the therapeutically effective dose to reach. Preferred unit dosage formulations are those containing a daily dose, or less than that described above or a suitable portion thereof. Furthermore, such pharmaceutical formulations can be prepared by any method well known in the pharmaceutical art.

  The pharmaceutical formulation can be administered by any suitable route, eg, oral (buccal or sublingual), rectal, nasal, topical (buccal, sublingual or transdermal), vaginal or parenteral (subcutaneous, intramuscular, intravenous or intradermal). ) Suitable for administration by route. Such formulations can be prepared by any method known in the pharmaceutical art, for example, by mixing the active ingredient with a carrier, diluent and / or excipient.

  Capsules (including soft gelatin capsules, hard gelatin capsules and capsules made from other polymers such as hydroxypropyl methylcellulose) or discrete units such as tablets, powders or granules, solutions, emulsions or suspensions in aqueous or non-aqueous liquids Pharmaceutical formulations suitable for oral administration can be provided as suspensions, edible foams or whips, or oil-in-water liquid emulsions or water-in-oil emulsions. For example, for oral administration in the form of a tablet or capsule (eg, hard, soft, elastic, gelatinous and / or nongelatinous) the active drug ingredient can be pharmaceutically acceptable, such as ethanol, glycerin, water, etc. It can be combined with an oral and non-toxic inert carrier. Powders are prepared by milling the compound to a suitable fine size and mixing with a similarly finely divided pharmaceutical carrier such as an edible carbohydrate such as starch or mannitol. Perfumes, preservatives, opacifiers, dispersants and colorants or dyes may be present.

  Capsules are prepared by preparing a powder mixture as described above and filling a shaped gelatin and / or non-gelatin sheath. Prior to the filling operation, glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture. Disintegrants or solubilizers such as agar, calcium carbonate or sodium carbonate can also be added to improve the effectiveness of the medicament when the capsule is ingested.

  In addition, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be added to the mixture. Suitable binders include natural sugars such as starch, gelatin, glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, cellulose polymers (eg hydrogels (HPMC, HPC, PVA), etc.), carboxymethylcellulose, polyethylene glycol, wax, polyvinylpyrrolidone and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum and the like. For example, tablets are formulated by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and compressing into tablets. Appropriately comminuted compounds with said diluent or base and optionally further binders such as carboxymethylcellulose, alginate, gelatin or polyvinylpyrrolidone, dissolution retardants such as paraffin, absorption enhancers such as quaternary salts and / or A powder mixture is prepared by mixing with an absorbent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a syrup, starch paste, acadia gum or a solution of cellulose or polymer material, etc. and passing through a sieve. Instead of granulation, the powder mixture can be run through a tablet machine, the result being an incompletely shaped slag that is ground into granules. Lubricating the granules by adding stearic acid, stearate, talc or mineral oil can prevent sticking to the tablet mold. The lubricated mixture is then compressed into tablets. When the compounds of the invention are combined with a free-flowing inert carrier, they can be compressed directly into tablets without going through a granulation or slagging step. A clear or turbid protective coating consisting of a shellac sealing coating, a coating consisting of a sugar or polymer material (eg HPMC) and a polish coating consisting of a wax may also be provided. Dyestuffs can also be added to these coatings to distinguish individual unit agents.

  The drug can also be dissolved or dispersed in a volatile liquid such as water or ethanol and sprayed onto non-pareil beads. Binders such as sucrose, polyvinyl pyrrolidone, and hydroxypropyl methylcellulose can also be used. The at least one coating can be followed by a protective coat made of a polymer such as hydroxypropylmethylcellulose and / or a sustained or delayed release coating. The beads thus coated are optionally compressed into tablets or filled into capsules.

  Oral fluids such as solutions, syrups and elixirs are prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient. While syrups can be prepared by dissolving the compound in an appropriately perfumed aqueous solution, elixirs are prepared through the use of a non-toxic alcohol vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizing and emulsifying agents such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, flavors such as mint oil or natural sweeteners or saccharin or other artificial sweeteners can also be added.

  Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared such that release is extended or sustained, for example, by coating or by embedding particulate matter in polymers, waxes, and the like. Compounds of formula (I) can also be incorporated into candy, wafer and / or tongue tape formulations for administration as “rapid dissolution” pharmaceuticals. Oral dosage forms can be taken with or without water.

  In addition, the present invention is combined with at least one selected from the group consisting of at least one drug or drug for treating obesity, diabetes (eg, rosiglitazone and / or metformin), hypertension and arteriosclerosis. In the form of a compound of formula (I). In particular, the compound of formula (I) is transformed into human ciliary neurotrophic factor, CB-1 antagonist or inverse agonist (such as rimonabant), neurotransmitter reuptake inhibitor (such as sibutramine, bupropion or bupropion HCl), lipase inhibitor. (Such as orlistat), MC4R agonists, 5-HT2c agonists and ghrelin receptor agonists or antagonists can be combined with at least one species for treating obesity.

  Furthermore, the present invention also provides the use of a compound of formula (I) for the manufacture of a medicament (medicament) for treating a condition selected from the group consisting of obesity, diabetes, depression and anxiety in a mammal. is there.

  The following examples are intended solely for the purpose of illustration and are in no way intended to limit the scope of the invention, which is defined by the appended claims. All references cited herein are hereby incorporated by reference.

  Reagents are commercially available or are prepared according to procedures described in the literature.

6- (4-Chlorophenyl) -3- {2-[(dimethylamino) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: 6-Nitroquinoline-2-carbaldehyde To a warm solution of selenium dioxide (41.6 g, 375 mmol) in dioxane (185 mL) and water (35 mL) was added 2-methyl-6-nitroquinoline (47.0 g, 250 mmol) was added. The mixture was refluxed for 30 minutes. Selenium black was filtered off and the filtrate was concentrated by rotary evaporation. The resulting solid was filtered, washed with a saturated solution of sodium bicarbonate, then water and dried to give the product as a tan solid (44.8 g, 89%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 9.21 (d, J = 2.6 Hz, 1H), 8.97 (d, J = 8.5 Hz, 1H), 8.59 (dd, J = 2.6 Hz, J ′ = 9.2 Hz, 1H), 8.44 (d, J = 9.2 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H) ).

Step B: N, N-dimethyl-1- (6-nitroquinolin-2-yl) methanamine 6-nitroquinoline-2-carbaldehyde in Example 1, Step A in dichloroethane (800 mL) and methanol (320 mL) To a solution of the prepared intermediate, 44.8 g, 221 mmol) was added dimethylamine (221 mL, 442 mmol, 2M in THF) and acetic acid (13.3 g, 221 mmol). The mixture was stirred at room temperature for 20 minutes, at which time 3 drops of sodium triacetoxyborohydride (65.6 g, 309 mmol) were added with vigorous mechanical stirring. The reaction mixture was stirred overnight. To the reaction mixture was added saturated sodium bicarbonate solution (300 mL) and the mixture was extracted with dichloromethane (2 × 400 mL). The organic layer was filtered through celite. The filtrate was washed with brine (200 mL), dried and concentrated to give a tan solid (41.1 g, 80% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.05 (d, J = 2 Hz), 8.67 (d, J = 9.6 Hz, 1 H), 8.43 (dd, J = 2.2 Hz, J '= 12.3 Hz), 8.17 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 8.6 Hz, 1H), 3.75 (s, 2H), 2.24 ( 2,6H).

Step C: 2-[(Dimethylamino) methyl] -6-quinolinamine N, N-dimethyl-1- (6-nitroquinolin-2-yl) methanamine (intermediate prepared in Example 1, Step B, 365 mg, 1.58 mmol) was dissolved in EtOH. A catalytic amount of Pd / C was added. The mixture was degassed and stirred under 1 atm of H ₂ for 5 hours. The mixture was filtered through celite and the solvent was removed to give the desired intermediate (290 mg, 91%). ¹ H NMR (CDCl ₃ ): δ 2.30 (6H, s), 3.68 (2H, s), 6.87 (1H, m), 7.11 (1, m), 7.15 (1H, s), 7.43 (1H, d, J = 8.8 Hz), 7.86 (1H, m). LCMS m / z = 202 (m + H ^< + ^> ).

Step D: Methyl 5- (4-chlorophenyl) -3-{[(E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate 3-amino-5- (4-chlorophenyl) -2-thiophenecarboxylic A mixture of ethanol (350 mL) consisting of methyl acid (37.3 mmol, 10.0 g) and N, N-dimethylformamide dimethyl acetal (74.7 mmol, 8.9 g) was heated to reflux for 3 hours. The solvent was removed by rotary evaporation. To the residue was added 15 mL of toluene and the solvent was removed by rotary evaporation. This was repeated three times. To the resulting viscous residue, 20 mL of hexane was added, followed by slow addition of ethyl acetate at 0 ° C. until solidified. The resulting solid was collected by filtration to give the desired intermediate (11.9 g, 98.9%). ¹ H NMR (CDCl ₃ ): δ 3.08 (6H, d, J = 6.5 Hz), 3.81 (3H, s), 6.98 (1H, s), 7.35 (2H, d, J = 8.6 Hz), 7.53 (2H, d, J = 8.5 Hz), 7.69 (1 H, s). LCMS m / z = 323 (m + H ^< + ^> ).

Step E: 6- (4-Chlorophenyl) -3- {2-[(dimethylamino) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidin-4 (3H) -one AlMe _{3 in} hexane 2M solution (0.96 mL, 19.2 mmol) of 2-[(dimethylamino) methyl] -6-quinolin-6-amine (the intermediate prepared in Example 1, Step C, 0.34 g, 1. 69 mmol) in dichloromethane (6 mL) was slowly added under N ₂ at room temperature. After 15 minutes, methyl 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate (intermediate prepared in Example 1, Step D, 0 (50 g, 1.54 mmol) in dichloroethane (3 mL) was added and stirred at room temperature for 0.5 hour. The solution was heated to reflux for 3 hours and then cooled to room temperature. Formic acid (6 mL) was added carefully and the mixture was heated to reflux for 4 hours. Upon cooling to room temperature, 1N aqueous NaOH (50 mL) was added followed by CH ₂ Cl ₂ (400 mL) and water (300 mL). The organic layer was separated, dried over MgSO ₄ , filtered and concentrated to 6- (4-chlorophenyl) -3- {2-[(dimethylamino) methyl] quinolin-6-yl} thieno [3,2 -D] Pyrimidin-4 (3H) -one (title compound) was obtained as a tan solid (0.79 g) with a purity of about 85%. This solid was partially dissolved in warm CHCl ₃ (20 mL), filtered and concentrated. The resulting solid was dissolved in CHCl ₃ (15 mL) and then Et ₂ O (25 mL) was added, which produced a white precipitate. The solid was filtered and dried under vacuum to give 6- (4-chlorophenyl) -3- {2-[(dimethylamino) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidine-4. (3H) -one (title compound) was obtained as a white powder (0.33 g, 48%). Subsequently, the remaining impure material was purified in the same manner as described above to additionally obtain 0.10 g of the title compound (overall yield 63%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.26 (d, J = 7.9 Hz, 1H), 8.25 (s, 1H), 8.21 (d, J = 8.2 Hz, 1H), 7. 91 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 2.4, 9.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.68 (D, J = 8.8 Hz, 2H), 7.57 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 3.83 (s, 2H), 2.37 (s , 6H). EI-LCMS m / z 447 (M + H).

6- (4-Chlorophenyl) -3- {2-[(4-phenylpiperidin-1-yl) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: 2- (Bromomethyl) -6-nitroquinoline 2-Methyl-6-nitroquinoline (3.0 g, 15.9 mmol) and N-bromosuccinimide (3.11 g, 17.49 mmol) in a Pyrex round bottom flask A chloroform solution (36 mL) consisting of was stirred at 40 ° C. for 2 days in the presence of a UV lamp. After cooling, the mixture was washed with aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate. Concentration followed by column chromatography on silica gel using hexane: ethyl acetate (7: 3) gave 2- (bromomethyl) -6-nitroquinoline as a pale yellow solid (2.67 g, 63%). Obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.10 (s, 1H), 8.78 (d, J = 8.6 Hz, 1H), 8.52 (d, J = 9.8 Hz, 1H), 8.23 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 4.93 (s, 2H); ES-LCMS m / z 267 (M + H).

Step B: 6-Nitro-2-[(4-phenylpiperidin-1-yl) methyl] quinoline 2- (Bromomethyl) -6-nitroquinoline (Example 2, intermediate prepared in Step A, 1.0 g HUNIG base (1.31 mL, 7.52 mL) was added to a THF solution of 3.76 mmol) at room temperature, followed by 4-phenylpiperidine (0.61 g, 3.76 mmol). The contents were stirred for 3 hours at room temperature. The crude reaction mixture was concentrated and loaded directly onto a silica gel column using hexane: ethyl acetate (1: 1) as eluent to give 6-nitro-2-[(4-phenylpiperidin-1-yl) methyl] quinoline. Was obtained as a brown solid (1.05 g, 81%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.03 (s, 1H), 8.67 (d, J = 9.0 Hz, 1H), 8.43 (d, J = 9.4 Hz, 1H), 8.16 (d, J = 9.4 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.29 to 7.14 (m, 5H), 3.83 (s, 2H) ), 2.94 (m, 2H), 2.51 (m, 2H), 2.23 (m, 2H), 1.73-1.67 (m, 3H); ES-LCMS m / z 348 ( M + H).

Step C: 2-[(4-Phenylpiperidin-1-yl) methyl] quinolin-6-amine 6-nitro-2-[(4-phenylpiperidin-1-yl) methyl] quinoline (Example 2, Step B) To a 30 mL THF / EtOH (1: 1) solution of the intermediate prepared in 1.0 g, 2.88 mmol), 0.1 g Pd / C (10%) was added and the contents were added under hydrogen gas (40 psi) For 6 hours. The reaction was then filtered through celite, washed with EtOH, and the contents were concentrated in vacuo to give 2-[(4-phenylpiperidin-1-yl) methyl] quinolin-6-amine as a green solid (0 8 g, 87%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.91 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 8 .5Hz, 1H), 7.39-7.10 (m, 6H), 6.78 (s, 1H), 3.45 (s, 2H), 2.94 (m, 2H), 2.52 ( m, 2H), 2.16 (m, 2H), 1.74-1.65 (m, 3H); ES-LCMS m / z 320 (M + H).

Step D: 6- (4-Chlorophenyl) -3- {2-[(4-phenylpiperidin-1-yl) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidine-4 (3H)- On 2-[(4-Phenylpiperidin-1-yl) methyl] quinolin-6-amine (Example 2, intermediate prepared in Step C, 0.160 g, 0.506 mmol) to 5- (4-chlorophenyl) ) -3-{[(1E)-(Dimethylamino) methylidene] amino} methyl thiophene-2-carboxylate (0.163 g, 0.506 mmol) and 0.5 g phenol as solvent were added. The reaction mixture was heated from 100 ° C. to 135 ° C. over 1.5 hours. When the crude mixture was loaded onto a silica gel column using DCM / MeOH (95: 5), 6- (4-chlorophenyl) -3- {2-[(4-phenylpiperidin-1-yl) methyl] quinoline- 6-yl} thieno [3,2-d] pyrimidin-4 (3H) -one (title compound) was obtained as a yellow solid (0.085 g, 30%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.61 (s, 1H), 8.59 (s, 1H), 8.32 (s, 1H), 8.25 (d, J = 9.0 Hz, 1H), 8.03 to 7.90 (m, 5H), 7.60 (d, J = 8.4 Hz, 1H), 7.35 to 7.21 (m, 6H), 4.76 (s, 2H), 3.61 to 3.49 (m, 2H), 3.28 to 3.15 (m, 2H), 2.87 (m, 1H), 2.22 to 1.96 (m, 4H) ES-LCMS m / z 563 (M + H).

6- (4-Chlorophenyl) -3- {2-[(4-phenylpiperazin-1-yl) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: 6-Nitro-2-[(4-phenylpiperazin-1-yl) methyl] quinoline Using the same experimental procedure as in Example 2, Step B, 2- (bromomethyl) -6-nitroquinoline 6-nitro-2-[(4-phenylpiperazin-1-yl) methyl] quinoline was prepared by reacting 1-phenylpiperazine with 1-phenylpiperazine. The compound was purified by column chromatography on silica gel, eluting with a gradient of 40% ethyl acetate in hexane. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 8.69 (d, J = 8.6 Hz, 1H), 8.45 (d, J = 9.1 Hz, 1H), 8.18 (d, J = 9.1 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.20 (m, 2H), 6.92 (m, 2H), 6. 77 (m, 1H) 3.87 (s, 2H), 2.61 (m, 4H), 2.48 (m, 4H); ES-LCMS m / z 349 (M + H).

Step B: 2-[(4-Phenylpiperazin-1-yl) methyl] quinolin-6-amine Using an experimental procedure similar to Example 2, Step C, using 6-nitro-2-[(4-phenyl By reacting piperazin-1-yl) methyl] quinoline (Example 3, Step A) with hydrogen gas and 10% Pd / C, 2-[(4-phenylpiperazin-1-yl) methyl] quinoline- A 6-amine was prepared. The crude compound was used as such in the next step. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.92 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 8 .4 Hz, 1H), 7.21 to 7.12 (m, 3H), 6.92 (m, 2H), 6.79 (m, 2H), 5.53 (s, 2H), 3.69 ( s, 2H), 3.14 (m, 4H), 2.58 (m, 4H); ES-LCMS m / z 319 (M + H).

Step C: 6- (4-Chlorophenyl) -3- {2-[(4-phenylpiperazin-1-yl) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidine-4 (3H)- On Using the same experimental procedure as in Example 2, Step D, 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thiophene-2-carboxylate (implemented) Example 1, Step D) is reacted with 2-[(4-phenylpiperazin-1-yl) methyl] quinolin-6-amine to give 6- (4-chlorophenyl) -3- {2-[(4 -Phenylpiperazin-1-yl) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidin-4 (3H) -one was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.62 (s, 1H), 8.60 (s, 1H), 8.32 (s, 1H), 8.25 (d, J = 9.0 Hz, 1H), 8.03 to 7.94 (m, 4H), 7.84 (d, J = 8.4 Hz, 1H), 7.60 (m, 2H), 7.28 (m, 1H), 7 .16 (m, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.87 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H), 4.84 (s, 2H), 3.54 (m, 4H), 2.07 (m, 4H); ES-LCMS m / z 564 (M + H).

6- (4-Chlorophenyl) -3- [2- (morpholin-4-ylmethyl) quinolin-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: 2- (Morpholin-4-ylmethyl) -6-nitroquinoline Using the same experimental procedure as in Example 2, Step B, react 2- (bromomethyl) -6-nitroquinoline with morpholine. Thus, 2- (morpholin-4-ylmethyl) -6-nitroquinoline was prepared. The desired compound was purified by column chromatography on silica gel eluting with a gradient of 80% ethyl acetate in hexane. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.08 (s, 1H), 8.72 (d, J = 8.6 Hz, 1H), 8.48 (d, J = 9.1 Hz, 1H), 8.21 (d, J = 9.2 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 3.89 (s, 2H), 3.66 (m, 4H), 2. 54 (m, 4H); ES-LCMS m / z 274 (M + H).

Step B: 2- (morpholin-4-ylmethyl) quinolin-6-amine Using the same experimental procedure as in Example 2, Step C, 6-nitro-2-[(4-phenylpiperazin-1-yl 2-) (Morpholin-4-ylmethyl) quinolin-6-amine was prepared by reducing methyl) quinoline with hydrogen gas and 10% Pd / C. The crude compound was used as such in the next step. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.93 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 8 .5Hz, 1H), 7.21 to 7.11 (m, 1H), 6.81 (m, 1H), 5.55 (s, 2H), 3.65 (s, 2H), 3.61 ( m, 4H), 2.51 (m, 4H); ES-LCMS m / z 244 (M + H).

Step C: 6- (4-Chlorophenyl) -3- [2- (morpholin-4-ylmethyl) quinolin-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one Example 2, Step Using the same experimental procedure as in D, 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thiophene-2-carboxylate (Example 1, Step D) The title compound was prepared by reacting with 2- (morpholin-4-ylmethyl) quinolin-6-amine (Example 4, Step B). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.57 (s, 1H), 8.42 (d, J = 8.6 Hz, 1H), 8.19 (s, 1H), 8.12 (d, J = 9.0 Hz, 1H), 8.01 (s, 1H), 7.95-7.90 (m, 3H), 7.75 (d, J = 8.4 Hz, 1H), 7.59 ( m, 2H), 3.79 (s, 2H), 3.61 (m, 4H), 2.48 (m, 4H); ES-LCMS m / z 509 (M + H).

6- (4-Chlorophenyl) -3- {2-[(4-methylpiperazin-1-yl) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: 2-[(4-Methylpiperazin-1-yl) methyl] -6-nitroquinoline Using the same experimental procedure as in Example 2, Step B, 2- (bromomethyl) -6-nitroquinoline 2-[(4-methylpiperazin-1-yl) methyl] -6-nitroquinoline was prepared by reacting 1-methylpiperazine with 1-methylpiperazine. The desired compound was purified by column chromatography on silica gel eluting with 100% ethyl acetate. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.09 (s, 1H), 8.73 (d, J = 8.5 Hz, 1H), 8.49 (d, J = 9.3 Hz, 1H), 8.21 (d, J = 9.3 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 3.89 (s, 2H), 2.75 (m, 4H), 2. 54 (m, 4H), 2.45 (s, 3H); ES-LCMS m / z 287 (M + H).

Step B: 2-[(4-Methylpiperazin-1-yl) methyl] quinolin-6-amine Using the same experimental procedure as in Example 1, Step C, 6-nitro-2-[(4- 2-[(4-Methylpiperazin-1-yl) methyl] quinolin-6-amine was prepared by reducing phenylpiperazin-1-yl) methyl] quinoline with hydrogen gas and 10% Pd / C. The crude compound was used as such in the next step. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.95 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 8 .6 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.81 (s, 1H), 5.57 (s, 2H), 3.71 (s, 2H), 2. 76 (m, 4H), 2.53 (m, 4H), 2.43 (s, 3H); ES-LCMS m / z 257 (M + H).

Step C: 6- (4-Chlorophenyl) -3- {2-[(4-methylpiperazin-1-yl) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidine-4 (3H)- On Using the same experimental procedure as in Example 2, Step D, 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thiophene-2-carboxylate (implemented) The title compound was prepared by reacting Example 1, Step D) with 2-[(4-Methylpiperazin-1-yl) methyl] quinolin-6-amine (Example 5, Step B). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.56 (s, 1H), 8.42 (d, J = 8.6 Hz, 1H), 8.19 (s, 1H), 8.11 (d, J = 9.0 Hz, 1H), 8.02 (s, 1H), 7.94-7.88 (m, 3H), 7.75 (d, J = 8.5 Hz, 1H), 7.59 ( m, 2H), 3.82 (s, 2H), 2.64-2.37 (m, 11H); ES-LCMS m / z 502 (M + H).

6- (4-Chlorophenyl) -3- (2-{[(3R) -3-hydroxypyrrolidinyl] methyl} -6-quinolinyl) thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: (3R) -1 [(6-Nitro-2quinolinyl) methyl] -3-pyrrolidinol Using the technique described in Example 1, Step B, (3R) -hydroxypyrrolidine and 6-nitroquinoline- This intermediate was prepared from 2-carbaldehyde. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.77 (s, 1H); 8.69 (d, J = 9.6 Hz, 1H); 8.30 (d, J = 8.4 Hz, 1H); 17 (d, J = 9.2 Hz, 1H); 7.75 (d, J = 8.4 Hz, 1H); 4.41 to 4.39 (m, 1H); 4.04 (s, 2H); 3.04 to 2.98 (m, 1H); 2.82 to 2.73 (m, 1H); 2.55 to 2.49 (m, 1H); 2.28 to 2.20 (m, 1H) ); 1.86-1.79 (m, 1H). ES-LCMS m / z 296 (M + Na).

Step B: (3R) -1-[(6-Amino-2-quinolinyl) methyl] -3-pyrrolidinol Prepared in Example 6, Step A using the technique described in Example 1, Step C. This intermediate was prepared from the intermediate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (d, J = 8.4 Hz, 1H); 7.79 (d, J = 9.2 Hz, 1H); 7.49 (d, J = 8 7.29 (d, J = 9.2 Hz, 1H); 6.97 (s, 1H); 4.62 (s, 2H); 4.41 (m, 1H); 48-3.39 (m, 2H); 3.26-3.14 (m, 2H); 2.19-2.02 (m, 1H); 1.95-1.85 (m, 1H). ES-LCMS m / z 244 (M + H).

Step C: 6- (4-Chlorophenyl) -3- (2-{[(3R) -3-hydroxypyrrolidinyl] methyl} -6-quinolinyl) thieno [3,2-d] pyrimidine-4 (3H) -On Using the technique described in Example 2, Step D, the title compound was obtained from the intermediate prepared in Example 6, Step B. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 to 8.17 (m, 3H); 7.89 (s, 1H); 7.74 (d, J = 8.4 Hz, 1H); 7.67 to 7.65 (m, 3H); 7.56 (s, 1H), 7.40 (d, J = 7.6 Hz, 2H); 4.40 (bs, 1H); 4.05 (s, 2H) 3.30-2.99 (m, 1H); 2.85-2.70 (m, 2H); 2.54-2.50 (m, 1H); 2.32-2.20 (m, 1H); 1.91 to 1.75 (m, 1H). ES-LCMS m / z 489 (M + H).

6- (4-Chlorophenyl) -3- {2-[(3-oxo-1-pyrrolidinyl) methyl] -6-quinolinyl} thieno [3,2-d] pyrimidin-4 (3H) -one Oxalyl chloride (dichloromethane) To a 2M medium solution, 5.5 mL, 11 mmol) at −60 ° C. was added DMSO (1.7 mL, 22 mmol) and the resulting mixture was stirred at this temperature for 5 min. In another flask, 6- (4-chlorophenyl) -3- (2-{[(3R) -3-hydroxypyrrolidinyl] methyl} -6-quinolinyl) thieno [3,2-d] pyrimidine-4 ( 3H) -one (33 mg, 0.67 mmol) was dissolved in 2 mL of dichloromethane. The oxidant solution prepared above (1.5 mL, 0.67 mmol) was added at −60 ° C. After the mixture was stirred for 15 minutes, 0.5 mL of triethylamine was added. The mixture was then allowed to warm to room temperature. The reaction was quenched by pouring the reaction mixture into saturated sodium bicarbonate solution. It was then partitioned between dichloromethane and an aqueous layer, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried and the solvent was removed by vacuum evaporation. The residue was purified by flash chromatography eluting with 3% methanol in dichloromethane. The title compound (26 mg) was obtained as a light tan solid. ¹ H NMR (400 MHz, CDCL3) δ 8.27 to 8.22 (m, 3H); 7.92 (s, 1H); 7.77 (d, J = 8.8 Hz, 1H); 7.69 to 7 7.56 (s, 1H); 7.46 (d, J = 8.4 Hz, 2H); 4.11 (s, 2H); 3.11 (s, 2H); 3.09 (t, J = 7.2 Hz, 2H); 2.49 (t, J = 7.4 Hz, 2H). ES-LCMS m / z 487 (M + H).

6- (4-Chlorophenyl) -3- (2-{[(3S) -3-fluoropyrrolidinyl] methyl} -6-quinolinyl) thieno [3,2-d] pyrimidin-4 (3H) -one dichloroethane 6- (4-Chlorophenyl) -3- (2-{[(3R) -3-hydroxypyrrolidinyl] methyl} -6-quinolinyl) thieno [3,2-d] pyrimidine in (1.5 mL) To 4 (3H) -one (title compound from Example 6, 20 mg, 0.04 mmol) was added diethylaminosulfur trifluoride (DAST, 10 mg, 0.06 mmol) at −30 ° C. The mixture was stirred overnight and allowed to warm to room temperature. The mixture was poured into ice-cold saturated sodium bicarbonate solution and extracted with dichloromethane. After the combined organic layers were washed and dried, the solvent was removed in vacuo. The residue was purified by flash chromatography eluting with 5% methanol in dichloromethane to give the title compound as a solid (12 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24-8.19 (m, 3H); 7.89 (s, 1H); 7.76-7.72 (m, 2H); 7.67 (d, J = 8.4 Hz, 2H); 7.56 (s, 1H); 7.45 (d, J = 8.4 Hz, 2H); 5.30-5.13 (m, 1H); 4.05 ( s, 2H); 3.03 to 2.82 (m, 2H); 2.60 (m, 1H); 2.28 to 2.04 (m, 2H). ES-LCMS m / z 490 (M + H).

[6- (6- (4-Chlorophenyl) -4-oxothieno [3,2-d] pyrimidin-3- (4H) -yl) -2-quinolinyl] methyl (methyl) formamide

Step A: N-methyl (6-nitro-2-quinolinyl) methanamine This intermediate was prepared from methylamine and 6-nitroquinoline-2-carbaldehyde using the technique described in Example 1, Step B. Was prepared.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 1H); 8.64 (d, J = 8, 8 Hz, 1H); 8.42 (d, J = 8.8 Hz, 1H); 8.13 (d, J = 9.2 Hz, 1H); 7.79 (d, J = 8.4 Hz, 1H); 3.98 (s, 2H); 2.32 (s, 3H). ES-LCMS m / z 218 (M + H).

Step B: t-Butyl methyl [(6-nitro-2-quinolinyl) methyl] carbamate (two rotamers)
The intermediate (1.4 g, 6.45 mmol) obtained in Example 9, Step A was dissolved in dichloromethane. Triethylamine (0.91 g, 9.03 mmol) and di-t-butyl dicarbonate (1.97 g, 9.03 mmol) were added. The reaction was stirred for 10 minutes, diluted with dichloromethane, washed sequentially with a saturated solution of sodium bicarbonate and sodium chloride, dried and concentrated to reduced pressure. The resulting residue was purified by flash chromatography using a 2: 1 hexane: ethyl acetate mixture as eluent to give 1.95 g (95% yield) of the desired intermediate as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.77 (bs, 1H); 8.46 (d, J = 9.2 Hz, 1H); 8.31 (bs, 1H); 8.14 (d, J = 8.8 Hz, 1H); 7.54-7.48 (m, 1H); 4.76 (s) and 4.72 (s), total 2H; 3.00 (s) and 2.93 ( s), 3H total; 1.51 (s) and 1.39 (s), 9H total. ES-LCMS m / z 318 (M + H).

Step C: t-Butyl (6-amino-2-quinolinyl) methyl (methyl) carbamate Starting with the intermediate prepared in Example 9, Step B, subjecting to the conditions described in Example 1, Step C This intermediate was prepared by ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.63 (d, J = 8.8 Hz, 1H); 8.14 (bs, 1H); 7.55 to 7.49 (m, 2H); 14 (bs, 1H); 4, 81 (s, 2H); 2.96 (bs, 3H); 1.40 (s) and 1.18 (s), 9H total. ES-LCMS m / z 288 (M + H).

Step D: [6- (6- (4-Chlorophenyl) -4-oxothieno [3,2-d] pyrimidin-3 (4H) -yl) -2-quinolinyl] methyl (methyl) formamide (rotamer)
The intermediate obtained in Example 9, Step C (430 mg, 1.5 mmol) is dissolved in 1,2-dichloroethane under a nitrogen atmosphere. A 2M trimethylaluminum solution in toluene (1.1 mL, 2.2 mmol) was added dropwise via a syringe. The mixture was stirred at room temperature for 20 minutes. Methyl 5- (4-chlorophenyl) -3-{[(1E) -dimethylamino) methylidene] -amino} thiophene-2-carboxylate (Example 1, intermediate from Step D, 483 mg, 1.5 mmol). In addition, the mixture was heated to reflux overnight. The solvent was removed under reduced pressure, and the resulting residue was dissolved in formic acid and heated to reflux for 2 hours. Formic acid was removed under reduced pressure, and the resulting residue was dissolved in dichloromethane, washed with a saturated solution of potassium carbonate, dried and concentrated under reduced pressure. Purification by flash chromatography using a 2-3% MeOH-dichloromethane mixture as eluent gave the title compound (150 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24-8.19 (m, 3H); 7.92 (d, J = 8.8 Hz, 1H); 7.78 (d, J = 8.8 Hz, 1H) 7.67 (d, J = 8.4 Hz, 2H); 7.57 (s, 1H); 7.50-7.40 (m, 3H); 4.87 (s) and 4.74 ( s), total 2H;); 3.02 (s) and 2.90 (s), total 3H. ES-LCMS m / z 461 (M + H).

6- (4-Chlorophenyl) -3- {2-[(methylamino) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: 1- (6-Nitroquinolin-2-yl) methanamine Methylamine (7.3 mL of a 2.0 M solution in tetrahydrofuran) was added 2- (bromomethyl) -6-nitroquinoline (0.86 g, 3.23 mmol). In 10 mL of tetrahydrofuran. The mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated and the crude product was purified by chromatography on silica gel. Elution with a 0-10% methanol gradient in dichloromethane gave 0.47 g (67%) of the desired product as a brown gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.1 (s, 1H), 8.71 (d, J = 8.5 Hz, 1H), 8.48 (d, J = 9.2 Hz, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 4.23 (s, 2H), 3.34 (brs, 1H) 50 (s, 3H). ES-LCMS m / z 218 (M + H).

Step B: t-butyl methyl [(6-nitroquinolin-2-yl) methyl] carbamate di (t-butyl) dicarbonate (0.71 g, 3.24 mmol) and triethylamine (0.30 mL, 2.16 mmol) Was added to a partial solution of N-methyl-1- (6-nitroquinolin-2-yl) methanamine (0.47 g, 2.16 mmol) in 20 mL of dichloromethane. The resulting homogeneous solution was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue purified by chromatography on silica gel using a 0-50% ethyl acetate gradient in hexanes to give 0.295 g (43%) of the desired product as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.07 (s, 1H), 8.70 (d, J = 8.6 Hz, 1H), 8.46 (d, J = 9.1 Hz, 1H), 8.15 (d, J = 9.3 Hz, 1H), 7.56 (m, 1H), 4.70 (s, 2H), 2.96 (m, 3H), 1.46 and 1.24 ( s, 9H).

Step C: t-Butyl (6-aminoquinolin-2-yl) methyl (methyl) carbamate In a Fisher-Porter tube, palladium (5 wt% supported on activated carbon, 0.098 g, 0.046 mmol) was added. To a solution of t-butyl methyl [(6-nitroquinolin-2-yl) methyl] carbamate (0.292 g, 0.92 mmol) in 20 mL of ethyl acetate. The mixture was evacuated and flushed with nitrogen, then evacuated and charged with 50 psi of hydrogen. After 1 hour, the reaction mixture was filtered through celite and the solvent was evaporated to give 0.254 g (96%) of the desired product as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.91 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.11 (d, J = 9 0.0 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.76 (s, 1H), 5.52 (s, 2H), 4.48 (s, 2H), 2. 82 (s, 3H), 1.43 and 1.31 (s, 9H).

Step D: (6-{[(5- (4-Chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thien-2-yl) carbonyl] amino} quinolin-2-yl) methyl T-butyl (methyl) carbamate 5- (4-chlorophenyl) -3-{[(1E) -dimethylamino) methylidene] -amino} thiophene-2-carboxylate methyl (Example 1, intermediate from Step D) , 0.067 g, 0.209 mmol) and (6-aminoquinolin-2-yl) methyl (methyl) carbamate t-butyl (0.050 g, 0.174 mmol) in 2 mL of anhydrous tetrahydrofuran was cooled to 0 ° C. . Sodium hexamethyldisilazane (0.26 mL of a 1.0 M solution in tetrahydrofuran) was added dropwise over 5 minutes. The mixture was stirred at 0 ° C. for 10 minutes and then allowed to warm to room temperature. After 2 hours, saturated aqueous ammonium chloride (0.5 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated. Chromatography on silica gel using a 0-100% ethyl acetate gradient in hexanes afforded 0.029 g (24%) of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.96 (s, 1 H), 8.49 (s, 1 H), 8.43 (d, J = 2.4 Hz, 1 H), 8.3 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.87 (s, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7. 76 (1/2 Abq, J = 8.6 Hz, 2H), 7.55 (1/2 Abq, J = 8.6 Hz, 2H), 7.32 (m, 1H), 4.61 (s, 2H), 3.24 and 3.22 (s, 6H), 2.90 (m, 3H), 1.46 and 1.31 (s, 9H). APCI-LCMS m / z 578 (M + H).

Step E: {6- [6- (4-Chlorophenyl) -4-oxothieno [3,2-d] pyrimidin-3 (4H) -yl] quinolin-2-yl} methyl (methyl) carbamate t-butyl catalyst The amount of p-toluenesulfonic acid was changed to (6-{[(5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thien-2-yl) carbonyl] amino} quinoline. 2-yl) methyl (methyl) carbamate t-butyl (0.025 g, 0.043 mmol) was added to a 5 mL absolute ethanol suspension. When heated to reflux, a homogeneous solution was obtained. After 2 hours, the mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in dichloromethane: methanol. Porous triethylammonium methylpolystyrene carbonate (0.050 mg, 0.14 mmol) was added and the mixture was stirred at room temperature for 18 hours. The resin was filtered off and the solution was concentrated to give the desired product as a white solid (0.023 mg, 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.57 (s, 1H), 8.44 (d, J = 8.6 Hz, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.01 (s, 1H), 7.94 (1/2 Abq, J = 8.6 Hz, 2H), 7.90 (d, J = 8.6 Hz, 1H), 7.58 (1/2 Abq, J = 8.6 Hz, 2H), 7.45 (m, 1H), 4.67 (s, 2H), 2.92 (m, 3H), 1.45 and 1. 28 (s, 9H). APCI-LCMS m / z 533 (M + H).

Step F: 6- (4-Chlorophenyl) -3- {2-[(methylamino) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetic acid (0 .050 mL) was converted to {6- [6- (4-chlorophenyl) -4-oxothieno [3,2-d] pyrimidin-3 (4H) -yl] quinolin-2-yl} methyl (methyl) carbamate t- To a solution of butyl (0.023 g, 0.043 mmol) in dichloromethane (2 mL) was added. The mixture was stirred at room temperature for 20 hours. The solvent was evaporated and 0.5 mL of methanol was added followed by 10 mL of diethyl ether. The mixture was filtered and the collected white solid was dried under reduced pressure to give 0.018 g (77%) of the title compound as the trifluoroacetate salt. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.15 (br s, 2H), 8.61 (s, 1H), 8.55 (d, J = 8.5 Hz, 1H), 8.31 (s , 1H), 8.20 (d, J = 9.1 Hz, 1H), 8.04 (s, 1H), 8.03 (d, J = 9.1 Hz, 1H), 7.96 (1/2 Abq , J = 8.6 Hz, 2H), 7.69 (d, J = 8.5 Hz, 1H), 7.61 (1/2 Abq, J = 8.6 Hz, 2H), 4.61 (s, 2H) 2.76 (s, 3H). ES-LCMS m / z 433 (M + H).

6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1-methyl-1H-benzimidazol-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: 2-Chloro-1-methyl-1H-benzimidazole Dimethyl sulfate (11 mL) was added 2-chlorobenzimidazole (10 g, 63.06 mmol) and 10 N NaOH (aq) in H ₂ O (115 mL) ( 15 mL) solution at 0 ° C. (via dropping funnel). The mixture was then allowed to warm to room temperature and then stirred at room temperature for 2 hours. TLC data (50% EtOAc / hexane) showed that 2-chlorobenzimidazole was consumed. A tan precipitate formed. The precipitate was filtered through a Buchner funnel, the filter cake was washed with H ₂ O, and the resulting precipitate was air dried to give a tan solid, 2-chloro-1-methyl-1H-benzimidazole (9.41 g, yield). Rate 90%) was obtained. ¹ H NMR (DMSO-d6) δ 7.56 (t, 2H, J = 14.5 Hz), 7.26 (m, 2H), 3.76 (s, 1H). ES-LCMS m / z 167 (100), (M + H).

Step B: A mixture of 2-chloro-1-methyl-5-nitro-1H-benzimidazole and 2-chloro-1-methyl-6-nitro-1H-benzimidazole concentrated H ₂ SO ₄ (20 mL) was performed. To a mixture consisting of the intermediate prepared in Example 11, Step A (9.41 g, 56.48 mmol) and concentrated HNO ₃ was added dropwise at 0 ° C. (via a dropping funnel). The mixture was stirred at 0 ° C. for 2 hours. TLC data (50% EtOAc / hexane) indicated that the starting material was consumed. The reaction mixture was poured into ice water (500 mL), the resulting yellow precipitate was filtered through a Buchner funnel, the filter cake was washed with H ₂ O, and the resulting precipitate was air dried to give 2-chloro-1 as a yellow solid. A mixture (8.78 g, 73% yield) of -methyl-5-nitro-1H-benzimidazole and 2-chloro-1-methyl-6-nitro-1H-benzimidazole was obtained. ¹ H NMR (DMSO-d6) δ 8.65 (s, 1H,), 8.47 (s, 1H), 8.21 (d, 1H, J = 11.2 Hz), 8.12 (d, 1H, J = 11.2 Hz), 7.82 (d, 1H, J = 9.0 Hz), 7.77 (d, 1H, J = 9 Hz), 3.89 (s, 1H), 3.85 (s, 1H). ES-LCMS m / z 212 (100), (M + H).

Step C: 2-Chloro-1-methyl-1H-benzimidazol-6-amine and 2-chloro-1-methyl-1H-benzimidazol-5-amine The intermediate prepared in Example 11, Step B (7 .78 g, 36.77 mmol) was added dropwise at room temperature to a solution of Sn (II) Cl ₂ .2H ₂ O (24.89 g, 110.30 mmol) in concentrated HCl (100 mL). The mixture was stirred at room temperature for 15 minutes and then at 100 ° C. for 1 hour. TLC data (30% CH ₃ CN / CH ₂ Cl ₂ ) indicated that the starting material was consumed. The reaction mixture was cooled to room temperature, brought to pH = 8 with 10N NaOH (aq), charged with Rochelle salt (100 mL) and then extracted with EtOAc (4 × 200 mL). The organics were dried over MgSO ₄ (anhydrous), filtered and concentrated to dryness. The resulting crude product is chromatographed on a SiO ₂ column (0-30% CH ₃ CN / CH ₂ Cl ₂ over 30 minutes, then 30% CH ₃ CN / CH ₂ Cl _{2 over} 60 minutes). Colored solid 2-chloro-1-methyl-1H-benzimidazol-5-amine (1.82 g, 27% yield) (in 30% CH ₃ CN / CH ₂ Cl ₂ , Rf = 0.18), ¹ H NMR (300 MHz, DMSO-d6) δ ppm 3.7 (s, 3H) 4.9 (s, 2H) 6.6 (dd, J = 8.6, 1.9 Hz, 1H) 6.7 ( d, J = 1.7 Hz, 1H) 7.2 (d, J = 8.6 Hz, 1H), ES-LCMS m / z 182 (60), (M + H), and pink solid 2-chloro-1 -Methyl-1H-benzimidazol-6-amine ( .5g, 52%) (in 30% _CH 3 CN / _{CH 2} Cl 2 ^{Yield, Rf = 0.33), 1 H} NMR (DMSO-d6) δ7.20 (d, 1H), 6.53 ( m, 2H), 5.09 (s, 2H), 3.60 (s, 3H), ES-LCMS m / z 182 (100), (M + H) were obtained.

Step D: N ² , N ² , 1-Trimethyl-1H-benzimidazole-2,6-diamine In a sealed tube, 2-chloro-1-methyl-1H-benzimidazol-6-amine (Example 11, Step C, 1 g, 5.51 mmol) and 2M dimethylamine in MeOH (30 mL) were stirred at 160 ° C. for 17.5 hours. TLC data (10% MeOH / CH ₂ Cl ₂ ) indicated that the starting material was consumed. The reaction mixture was cooled to room temperature and then concentrated to dryness. The resulting crude was chromatographed on a SiO ₂ column (0-6% MeOH / CH ₂ Cl _{2 over} 30 minutes, then 6% MeOH / CH ₂ Cl _{2 over} 30 minutes). Fractions corresponding to the product (10% MeOH / CH ₂ Cl ₂ in Rf = 0.34) were concentrated to dryness to give a pink solid N ² , N ² , 1-trimethyl-1H-benzimidazole-2 , 6-diamine (640 mg, 61% yield) was obtained. ¹ H NMR (DMSO-d6) δ 7.01 (d, 1H, J = 8.3 Hz), 6.42 (s, 1H), 6.36 (d, 1H, J = 10.3), 4.77 (S, 2H), 3.44 (s, 3H), 2.78 (s, 6H). ES-LCMS m / z 191 (100), (M + H).

Step E: 6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1-methyl-1H-benzimidazol-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one The intermediate from Example 11, Step D (1.09 g, 3.36 mmol) and Example 1, Step D (640 mg, 3.36 mmol) was mixed in phenol (5 g) and allowed to warm from room temperature over about 30 minutes. The mixture was stirred at 150 ° C. and then at 150 ° C. for 1 hour. LC-MS data showed that some starting material remained. The intermediate prepared in Example 1, Step D (300 mg, 0.93 mmol) was additionally added and the mixture was stirred at 150 ° C. for 1 hour. LC-MS data showed that the intermediate prepared in Example 11, Step D was consumed. The reaction mixture was cooled to about 60 ° C. and poured into MeOH (100 mL). The resulting precipitate was filtered, washed with MeOH and air dried to give the title compound as a tan solid (1.37 g, 93% yield). ¹ H NMR (DMSO-d6) δ 8.45 (s, 1H), 8.00 (s, 1H), 7.95 (d, 2H, J = 8.5 Hz), 7.58 (m, 3H), 7.47 (d, 1H, J = 8.3 Hz) 7.19 (d, 1H, J = 10.3), 3.65 (s, 3H), 2.98 (s, 6H). ES-LCMS m / z 436 (100), (M + H).

6- (4-Chlorophenyl) -3- [1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-indol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one hydrochloric acid salt

Step A: Ethyl 1-methyl-5-nitro-1H-indole-2-carboxylate Dissolve ethyl 5-nitro-1H-indole-2-carboxylate (1.75 g, 7.46 mmol) in DMF (30 mL), Sodium hydride (0.6 g of 60% dispersion) was added. The reaction was stirred at room temperature for 30 minutes. Methyl iodide (1.324 g, 9.33 mmol) was added. The reaction was stirred at room temperature overnight. The reaction solution was diluted with water (100 mL), and the precipitate was collected by suction filtration. The precipitate was taken up in EtOAc (100 mL), washed with water (2 × 50 mL) and dried over MgSO ₄ . Filtration and concentration gave 1.175 g (4.74 mmol, 63%) of product as a reddish brown solid. ¹ H NMR (CDCl ₃ ) δ 8.65 (d, 1 H, J = 2 Hz), 8.25 (dd, 1 H, J = 2.2 Hz, 11.3 Hz), 7.45 (s, 1 H), 7. 43 (d, 1H, J = 11.3 Hz), 4.40 (q, 2H, J = 7.1 Hz), 4.13 (s, 3H), 1.42 (t, 3H, J = 7.2 Hz) ).

Step B: (1-Methyl-5-nitro-1H-indol-2-yl) methanol ethyl 1-methyl-5-nitro-1H-indole-2-carboxylate (1.175 g, 4.74 mmol) in THF ( 50 mL). Alane (11 mL of 1M solution) was added. The reaction was heated to 70 ° C. and stirred for 6 hours, then cooled to room temperature, quenched with methanol (50 mL), diluted with water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organics were washed with water (3 × 150 mL), dried over MgSO ₄ , filtered and concentrated to give product 0.664 (3.22 mmol, 90%) as a reddish brown solid. ¹ H NMR (CDCl ₃ ) δ 8.54 (d, 1H, J = 2 Hz), 8.14 (dd, 1H, J = 2.2 Hz, 9.1 Hz), 7.35 (d, 1H, J = 9) .2 Hz), 6.62 (s, 1H), 4.82 (s, 2H), 3.90 (s, 3H).

Step C: 2- (Bromomethyl) -1-methyl-5-nitro-1H-indole (1-methyl-5-nitro-1H-indol-2-yl) methanol (0.664 g, 3.223 mmol) in CH ₂ Dissolved in Cl ₂ (50 mL). Carbon tetrabromide (1.336 g, 4.03 mmol) was added. The mixture was cooled to 0 ° C. and then triphenylphosphine (1.268 g, 4.83 mmol) was added in small portions over 1 hour. The reaction was stirred overnight, washed with water (1 × 100 mL), the organics dried over MgSO ₄ , filtered and concentrated. The mixture was filtered through a chromatatron plate to remove baseline impurities. The resulting solid was taken up in a minimum amount of CH ₂ Cl ₂ and triturated with hexanes to give 0.238 g (0.853 mmol, 26%) of the desired product as a yellow solid. ¹ H NMR (CDCl ₃ ) δ 8.55 (d, 1H, J = 2.2 Hz), 8.16 (dd, 1H, J = 2.2 Hz, 9.1 Hz), 7.35 (d, 1H, J = 9.1 Hz), 6.76 (s, 1H), 4.65 (s, 2H), 3.92 (s, 3H).

Step D: 1-Methyl-5-nitro-2- (pyrrolidin-1-ylmethyl) -1H-indole 2- (Bromomethyl) -1-methyl-5-nitro-1H-indole (0.134 g, 0.50 mmol) In DMF (5 mL). Pyrrolidine (0.060 mL, 0.75 mmol) was added along with triethylamine (0.134 mL, 1 mmol). The reaction was heated to 80 ° C., stirred for 2 hours, cooled to room temperature, and partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was removed and the organics were washed with water (3 × 50 mL), dried over MgSO ₄ , filtered and concentrated to give 0.112 g (0.432 mmol, 87%) of the product as a yellow semi-solid Obtained. ¹ H NMR (CDCl ₃ ) δ 8.50 (d, 1H, J = 2.2 Hz), 8.09 (dd, 1H, J = 2.2 Hz, 9.1 Hz), 7.30 (d, 1H, J = 9.1 Hz), 6.53 (s, 1H), 3.85 (s, 3H), 3.78 (s, 2H), 2.5 (bs, 4H), 1.8 (bs, 4H) .

Step E: 6- (4-Chlorophenyl) -3- [1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-indol-5-yl] thieno [3,2-d] pyrimidine-4 (3H) -On hydrochloride 1-methyl-5-nitro-2- (pyrrolidin-1-ylmethyl) -1H-indole (0.112 g, 0.43 mmol) was taken up in EtOAc (10 mL) and H _{2 on} a Parr hydrogenator. Hydrogenated via 10% Pd / C under 50 psi. After 2 hours, the mixture was filtered through celite and concentrated. The residue was taken up in a minimal amount of CH ₂ Cl ₂ and methyl 5- (4-chlorophenyl) -3-{[(dimethylamino) methylene] amino} thiophene-2-carboxylate (intermediate from Example 1, Step D). Body, 0.115 g, 0.43 mmol) and phenol (0.5 g) were added. The mixture was heated to 130 ° C., stirred for 30 minutes, cooled to room temperature and purified with chromatatron (from 100% CH ₂ Cl ₂ to 80:20 CH ₂ Cl ₂ : MeOH). The product was triturated with 1N HCl in Et ₂ O, stirred for 2 hours, and concentrated to give 0.071 g (0.139 mmol, 33%) of the title compound as a cream solid. ¹ H NMR (DMSO-d ₆ ) δ 10.2 (bs, 1H), 8.5 (s, 1H), 8.05 (s, 1H), 7.92 (d, 2H, J = 7.5 Hz) 7.77 (s, 1H), 7.67 (d, 1H, J = 8.8 Hz), 7.58 (d, 2H, J = 8.5 Hz), 7.34 (dd, 1H, J = 2.1 Hz, 8.1 Hz), 6.85 (s, 1H), 4.68 (d, 2H, J = 5.5 Hz), 3.2 (bs, 2H, 2.05 (bs, 2H), 1.95 (bs, 2H) LRMS M + H 475.

6- (4-Chlorophenyl) -3- (2-{[(2R) -2- (methoxymethyl) pyrrolidin-1-yl] methyl} -1-methyl-1H-indol-5-yl) thieno [3 2-d] pyrimidin-4 (3H) -one hydrochloride 6- (4-chlorophenyl) -3- [1-methyl-2- (pyrrolidin-1-ylmethyl) -1H-indol-5-yl] thieno [3 , 2-d] pyrimidin-4 (3H) -one hydrochloride using a procedure similar to that of Example 12 using (2R) -2- (methoxymethyl) pyrrolidine instead of pyrrolidine. The title compound was synthesized. ¹ H NMR (CDCl ₃ ) δ 12.9 (bs, 1H), 8.6 (s, 1H), 7.80 (s, 1H, 7.68 (d, 2H, J = 8.5 Hz), 7. 65 (s, 1H), 7.55 (d, 1H, J = 8.8 Hz), 7.48 (d, 2H, J = 8.5 Hz), 7.30 (d, 1H, J = 8.9 Hz) ), 6.80 (s, 1H), 4.94 (d, 1H, J = 14.3 Hz), 4.46 (m, 2H), 4.03 (s, 3H), 3.74-3. 60 (m, 2H), 3.55 (s, 3H), 3.00 (bs, 2H), 2.28 (bs, 1H), 2.17 (bs, 1H), 1.96 (bs, 2H) ) LRMS M + H 519.

6- (4-Methylphenyl) -3- [2- (pyrrolidin-1-ylmethyl) -1-benzofuran-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one maleate

Step A: 1-[(5-Nitro-1-benzofuran-2-yl) carbonyl] pyrrolidine 5-Nitro-1-benzofuran-2-carboxylic acid (0.50 g, 2.41 mmol) in thionyl chloride (5 mL). Suspended and heated to reflux. The reaction was stirred for 16 hours and then concentrated to dryness. The residue was taken up in DMF (5 mL) and pyrrolidine (0.343 g, 4.82 mmol) and triethylamine (0.488 g, 4.82 mmol) were added. The mixture was heated to 80 ° C. and stirred for 2 hours. The reaction mixture was then cooled to room temperature and water (50 mL) was added. The resulting solid was collected and taken up in EtOAc (50 mL). The organics were washed with water (3 × 150 mL), dried over MgSO ₄ , filtered and concentrated to give 0.454 g (1.75 mmol, 72%) of the title compound as a pale yellow solid. ¹ H NMR (CDCl ₃ ) δ 8.61 (dd, 1 H, J = 2.2 Hz), 8.32 (dd, 1 H, J = 2.2 Hz, 9.0 Hz), 7.63 (d, 1 H, J = 9.0 Hz), 7.51 (s, 1 H), 3.94 (t, 2 H, J = 6.8 Hz), 3.71 (t, 2 H, J = 7.0 Hz), 2.06 (p 2H, J = 6.7 Hz), 1.97 (p, 2H, J = 7.0 Hz).

Step B: 1-[(5-Nitro-1-benzofuran-2-yl) methyl] pyrrolidine 1-[(5-Nitro-1-benzofuran-2-yl) carbonyl] pyrrolidine (intermediate from Step A, 0 .363 g, 1.40 mmol) was suspended in anhydrous THF (5 mL). Alane (4 mL of 1M solution) was added and the mixture was heated to 70 ° C. and stirred for 2 hours. The mixture was then cooled to room temperature and quenched with methanol (10 mL). The mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organics were washed with water (3 × 50 mL), dried over MgSO ₄ , filtered and concentrated to give 0.210 g (0.854 mmol, 61%) of product as a dark gold oil. ¹ H NMR (CDCl ₃ ) δ 8.45 (d, 1H, J = 2.2 Hz), 8.19 (dd, 1H, J = 2.2 Hz, 8.8 Hz), 7.53 (d, 1H, J = 9 Hz), 6.74 (s, 1H), 3.85 (s, 2H), 2.65 (bs, 4H), 1.85 (bs, 4H).

Step C: 6- (4-Methylphenyl) -3- [2- (pyrrolidin-1-ylmethyl) -1-benzofuran-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -onmalein The acid salt 1-[(5-nitro-1-benzofuran-2-yl) methyl] pyrrolidine (intermediate from Step B, 0.210 g, 0.85 mmol) was placed in EtOAc (20 mL) and H ₂ (1 atm). Was hydrogenated over 10% Pd / C. The reaction was filtered through celite and concentrated. The resulting residue was taken up in a minimum amount of CH ₂ Cl ₂ . Phenol (0.5 g) and methyl 5- (4-chlorophenyl) -3-{[(dimethylamino) methylene] -amino} thiophene-2-carboxylate (Example 1, intermediate from Step D, 0.275 g) , 0.85 mmol). The mixture was heated to 130 ° C. and stirred for 1 hour, then cooled to room temperature and purified on chromatatron (100% CH ₂ Cl ₂ to 95: 5 CH ₂ Cl ₂ : MeOH). The isolated product was taken up in CH ₂ Cl ₂ (5 mL) and 1 equivalent of maleic acid was added. The mixture was stirred overnight and the precipitate was collected to give 0.089 g (0.154 mmol, 18%) of the title compound as a white solid. ¹ H NMR (DMSO-d ₆ ) δ 10.3 (bs, 1H), 8.5 (s, 1H), 7.99 (s, 1H), 7.92 (m, 3H), 7.80 (d , 1H, J = 8.8 Hz), 7.55 (m, 3H), 7.2 (s, 1H), 6.0 (s, 2H), 4.8 (bs, 2H), 3.4 ( bs 4H), 1.9 (bs, 4H). LRMS M + H 461

3- (2-{[(2R) -2- (methoxymethyl) pyrrolidin-1-yl] methyl} -1-benzofuran-5-yl) -6- (4-methylphenyl) thieno [3,2-d Pyrimidine-4 (3H) -one maleate 6- (4-Methylphenyl) -3- [2- (pyrrolidin-1-ylmethyl) -1-benzofuran-5-yl] thieno [3,2-d] Use a procedure similar to that for pyrimidine-4 (3H) -one maleate (Example 14) and use (2R) -2- (methoxymethyl) -pyrrolidine instead of pyrrolidine to give the title The compound was synthesized. ¹ H NMR (CDCl ₃ ) δ 8.3 (s, 1H), 7.80-7.75 (m, 3H), 7.6 (s, 1H), 7.5-7.4 (m, 3H) 7.10 (s, 1H) 6.4 (bs, 3H), 4.85-4.6 (bm, 2H), 4.0-3.8 (bs, 2H), 3.8-3. 7 (bs, 2H), 3.4 (s 3H), 3, 25 (bs, 1H), 2.29bs, 2H), 1.9 (bs, 2H). LRMS M + H 507.

6- (4-Chlorophenyl) -3- {2-[(dimethylamino) methyl] -2,3-dihydro-1,4-benzodioxin-6-yl} thieno [3,2-d] pyrimidine-4 ( 3H) -one 2-[(dimethylamino) methyl] -2,3-dihydro-1,4-benzodioxin-6-amine (prepared according to International Publication WO0121577, 0.100 g, 0.481 mmol) to 5 As methyl-(4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] -amino} thiophene-2-carboxylate (Example 1, Step D, 0.155 g, 0.481 mmol) and solvent 0.150 g of phenol was added. The reaction mixture was heated to 135 ° C. for 2 hours. When the crude mixture is loaded onto a silica gel column using DCM / MeOH (100: 5), 6- (4-chlorophenyl) -3- {2-[(dimethylamino) methyl] -2,3-dihydro-1, 4-Benzodioxin-6-yl} thieno [3,2-d] pyrimidin-4 (3H) -one (title compound) was obtained as a solid (0.096 g, 44%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.37 (s, 1H), 7.98 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 1.8 Hz, 1H), 7.03 (m, 2H), 4.40 (m, 2H), 4.04 (dd, J = 11.5 and 7.0 Hz, 1H), 2.56 (br, 2H), 2.27 (s, 6H); ES-LCMS m / z 454 (M + H).

6- (4-Chlorophenyl) -3- [2- (4-morpholinylmethyl) -2,3-dihydro-1,4-benzodioxin-6-yl] thieno [3,2-d] pyrimidine-4 The title compound was synthesized using the technique described in Example 16, substituting morpholine for (3H) -one dimethylamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.37 (s, 1H), 7.97 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 2.2 Hz, 1H), 7.02 (m, 2H), 4.46 (m, 1H), 4.38 (dd, J = 11.5 and 2.2 Hz, 1H), 4.06 (dd, J = 11.5 and 7.1 Hz, 1H), 3.59 (t, J = 14.6 Hz, 4H), 2.61 (m , 2H), 2.50 (br, 4H); ES-LCMS m / z 496 (M + H).

6- (4-Chlorophenyl) -3- [2- (4-methyl-1-piperazinyl) methyl] -2,3-dihydro-1,4-benzodioxin-6-yl] thieno [3,2-d] Pyrimidin-4 (3H) -one The title compound was synthesized using the technique described in Example 16, substituting 4-methyl-piperazine for dimethylamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.36 (s, 1H), 7.97 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 2.2 Hz, 1H), 7.02 (m, 2H), 4.42 (m, 1H), 4.36 (dd J = 11 .5 and 2.2 Hz, 1H), 4.04 (dd J = 11.5 and 7.2 Hz, 1H), 2.60 (d, J = 6.9 Hz, 2H), 2.50 (br, 4H) ), 2.33 (br, 4H), 2.16 (s, 3H); ES-LCMS m / z 509 (M + H).

6- (4-Chlorophenyl) -3- (2-{[(3R) -3-hydroxy-1-pyrrolidinyl] methyl} -2,3-dihydro-1,4-benzodioxin-6-yl) thieno [3 , 2-d] pyrimidin-4 (3H) -one The title compound was synthesized using the technique described in Example 16, substituting (3R) -3-hydroxy-pyrrolidine for dimethylamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.38 (s, 1H), 7.97 (s, 1H), 7.93 (d, d = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 2.0 Hz, 1H), 7.02 (m, 2H), 4.70 (br, 1H), 4.38 (m, 2H) 4.19 (m, 1H), 4.07 (m, 1H), 2.38-3.32 (m, 6H), 1.98 (m, 1H), 1.55 (m, 1H); ES-LCMS m / z 496 (M + H).

6- (4-Chlorophenyl) -3-{(2S) -2-[(dimethylamino) methyl] -2,3-dihydro-1,4-benzodioxin-6-yl} thieno [3,2-d] Pyrimidine-4 (3H) -one

Step A: 2-{[(Methyloxy) methyl] oxy} -5-nitrophenol To a solution of 4-nitrocatechol (12.7 g, 81.9 mmol) in anhydrous DMF in 100 mL, potassium carbonate (13.5 g, 97.8 mmol). And chloromethyl methyl ether (6.2 mL, 97.8 mmol) were added at 40 ° C. The mixture was stirred at this temperature for 1 hour and then the solvent was removed. Water was added and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Concentration followed by column chromatography on silica gel using a 4: 1 mixture of hexane: ethyl acetate yielded 2-{[(methyloxy) methyl] oxy} -5-nitrophenol as a solid (9.4 g, 58 %). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.80 (m, 2H), 7.18 (d, J = 8.8 Hz, 1H), 5.98 (s, 1H), 5.32 (s, 2H) 3.53 (s, 3H).

Step B: (2R) -2-{[(2-{[(methyloxy) methyl] oxy} -5-nitrophenyl) oxy] methyl} oxirane 2-{[(methyloxy) methyl] oxy} -5 To a solution of nitrophenol (1 g, 5 mmol), triphenylphosphine (3.95 g, 15 mmol) and (R) -glycidol (558 mg, 7.5 mmol) in 50 mL of anhydrous DCM, di-t-butyl azodicarboxylate (3 .47 g, 15 mmol) was added at room temperature. The reaction was stirred at room temperature overnight. Concentration followed by column chromatography on silica gel using a 4: 1 mixture of hexane: ethyl acetate as eluent gave (2R) -2-{[(2-{[(methyloxy) methyl] oxy}- 5-Nitrophenyl) oxy] methyl} oxirane was obtained as a solid (0.75 g, 59%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (dd, J = 9.0 and 2.5 Hz, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.22 (d, J = 9.0, 1H), 5.31 (s, 2H), 4.42 (dd, J = 11.3 and 2.6 Hz, 1H), 4.02 (dd, J = 11.3 and 6.3). 0 Hz, 1H), 3.52 (s, 3H), 3.42 (m, 1H), 2.94 (m, 1H), 2.79 (m, 1H); ES-LCMS m / z 278 (M + Na ).

Step C: 6- (4-Chlorophenyl) -3-{(2S) -2-[(dimethylamino) methyl] -2,3-dihydro-1,4-benzodioxin-6-yl} thieno [3,2 -D] pyrimidin-4 (3H) -one 2-((dimethylamino) methyl] -2,3-dihydro-1,4-benzodioxin-6-amine instead of (2S) -2-[(dimethylamino) ) Methyl] -2,3-dihydro-1,4-benzodioxin-6-amine ((2R) -2-{[(2-{[(methyloxy) methyl] oxy} -5 according to WO 0121577 pamphlet) The title compound was synthesized using the technique described in Example 16 using -nitrophenyl) oxy] methyl} oxirane (an intermediate prepared from Example 20, Step B). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.37 (s, 1H), 7.97 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 2.0 Hz, 1H), 7.02 (m, 2H), 4.38 (m, 2H), 4.03 (dd, J = 11.4 and 7.0 Hz, 1H), 2.54 (d, J = 6.0 Hz, 2H), 2.25 (s, 6H); ES-LCMS m / z 454 (M + H).

6- (4-Chlorophenyl) -3-{(2R) -2-[(dimethylamino) methyl] -2,3-dihydro-1,4-benzodioxin-6-yl} thieno [3,2-d] Pyrimidine-4 (3H) -one

Step A: (2S) -2-{[(2-{[(Methyloxy) methyl] oxy} -5-nitrophenyl) oxy] methyl} oxirane Instead of (R) -glycidol, (S) -glycidol Was used to synthesize this intermediate using the technique described in Example 20, Step B. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (dd, J = 9.0 and 2.6 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1 H), 5.31 (s, 2 H), 4.42 (dd, J = 11.4 and 2.7 Hz, 1 H), 4.03 (dd, J = 11.4 and 6. 0 Hz, 1H), 3.52 (s, 3H), 3.41 (m, 1H), 2.93 (m, 1H), 2.79 (m, 1H); ES-LCMS m / z 278 (M + Na ).

Step B: 6- (4-Chlorophenyl) -3-{(2R) -2-[(dimethylamino) methyl] -2,3-dihydro-1,4-benzodioxin-6-yl} thieno [3,2 -D] pyrimidin-4 (3H) -one (2R) -2-[(dimethylamino) instead of 2-[(dimethylamino) methyl] -2,3-dihydro-1,4-benzodioxin-6-amine ) Methyl] -2,3-dihydro-1,4-benzodioxin-6-amine ((2S) -2-{[(2-{[(methyloxy) methyl] oxy} -5 according to WO 0121577 pamphlet) The title compound was synthesized using the technique described in Example 16 using -nitrophenyl) oxy] methyl} oxirane (an intermediate prepared from Example 21, Step A). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.37 (s, 1H), 7.97 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 2.0 Hz, 1H), 7.02 (m, 2H), 4.38 (m, 2H), 4.03 (dd, J = 11.4 and 7.0 Hz, 1H), 2.54 (d, J = 6.2 Hz, 2H), 2.25 (s, 6H); ES-LCMS m / z 454 (M + H).

6- (4-Chlorophenyl) -3-[(2S) -2- (1-pyrrolidinylmethyl) -2,3-dihydro-1,4-benzodioxin-6-yl] thieno [3,2-d ] Pyrimidin-4 (3H) -one The title compound was synthesized using the technique described in Example 20 using pyrrolidine instead of dimethylamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.37 (s, 1H), 7.97 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 2.0 Hz, 1H), 7.01 (2H), 4.38 (m, 2H), 4.05 (dd, J = 11.1. 7 and 7.3 Hz, 1H), 2.75 (m, 2H), 2.67 (m, 4H), 1.70 (s, 4H); ES-LCMS m / z 480 (M + H).

6- (4-Chlorophenyl) -3-[(2R) -2- (1-pyrrolidinylmethyl) -2,3-dihydro-1,4-benzodioxin-6-yl] thieno [3,2-d ] Pyrimidin-4 (3H) -one The title compound was synthesized using the technique described in Example 21 using pyrrolidine instead of dimethylamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.37 (s, 1H), 7.97 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 2.2 Hz, 1H), 7.01 (2H), 4.38 (m, 2H), 4.05 (dd, J = 11.1. 8 and 7.4 Hz, 1H), 2.73 (m, 2H), 2.57 (m, 4H), 1.70 (s, 4H); ES-LCMS m / z 480 (M + H).

6- (4-Chlorophenyl) -3- {2-[(dimethylamino) methyl] -3,4-dihydro-2H-1,4-benzoxazin-6-yl} thieno [3,2-d] pyrimidine- 4 (3H) -one 2-[(dimethylamino) methyl] -3,4-dihydro instead of 2-[(dimethylamino) methyl] -2,3-dihydro-1,4-benzodioxin-6-amine The title compound was synthesized using the technique described in Example 16 using -2H-1,4-benzodioxin-6-amine (an intermediate prepared according to WO 0121577). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 7.96 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 6.58 (dd, J = 8.4) And 2.5 Hz, 1H), 6.14 (s, 1H), 4.19 (m, 1H), 3.38 (m, 1H), 3.05 (m, 1H), 2.50 (br, 2H), 2.25 (s, 6H); ES-LCMS m / z 453 (M + H).

6- (4-Chlorophenyl) -3- [2- (4-morpholinylmethyl) -3,4-dihydro-2H-1,4-benzoxazin-6-yl] thieno [3,2-d] pyrimidine -4 (3H) -one The title compound was synthesized using the technique described in Example 24, using morpholine instead of dimethylamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (s, 1H), 7.92 (s, 1H), 7.89 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 2.5 Hz, 1H), 6.54 (dd, J = 8.4) And 2.5 Hz, 1H), 6.10 (s, 1H), 4.21 (m, 1H), 3.56 (t, J = 4.6 Hz, 4H), 3.38 (m, 1H), 3.05 (m, 1H), 2.39 to 2.53 (m, 6H); ES-LCMS m / z 495 (M + H).

6- (4-Chlorophenyl) -3- [2- (1-pyrrolidinylmethyl) -3,4-dihydro-2H-1,4-benzoxazin-6-yl] thieno [3,2-d] pyrimidine -4 (3H) -one The title compound was synthesized using the technique described in Example 24, using pyrrolidine instead of dimethylamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (s, 1H), 7.92 (s, 1H), 7.89 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 2.5 Hz, 1H), 6.55 (d, J = 8.4) And 2.5 Hz, 1H), 6.09 (s, 1H), 4.15 (m, 1H), 3.36 (m, 1H), 3.04 (m, 1H), 2.46-2. 67 (m, 6H), 1.67 (br, 4H); ES-LCMS m / z 479 (M + H).

6- (4-Chlorophenyl) -3- {2-[(4-methyl-1-piperazinyl) methyl] -3,4-dihydro-2H-1,4-benzoxazin-6-yl} thieno [3,2 -D] pyrimidin-4 (3H) -one The title compound was synthesized using the technique described in Example 24, using 4-methyl-piperazine instead of dimethylamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.34 (s, 1H), 7.95 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.67 (d, 2.4 Hz, 1H), 6.57 (dd, J = 8.4 and 2). .4 Hz, 1 H), 6.12 (s, 1 H), 4.21 (m, 1 H), 3.39 (m, 1 H), 3.06 (m, 1 H), 2.20 to 2.58 ( m, 10H), 2.16 (s, 3H); ES-LCMS m / z 508 (M + H).

6- (4-Chlorophenyl) -3- (2-{[(3R) -3-hydroxy-1-pyrrolidinyl] methyl} -3,4-dihydro-2H-1,4-benzoxazin-6-yl) thieno [3,2-d] pyrimidin-4 (3H) -one The title compound was synthesized using the technique described in Example 24, replacing dimethylamine with (3R) -3-hydroxypyrrolidine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.34 (s, 1H), 7.95 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 6.57 (dd, J = 8.4) And 2.5 Hz, 1H), 6.12 (s, 1H), 4.70 (m, 1H), 4.17 (m, 1H), 3.38 (m, 1H), 3.08 (m, 1H), 2.36-2.84 (m, 6H), 1.98 (m, 1H), 1.54 (m, 1H); ES-LCMS m / z 495 (M + H).

6- (4-Chlorophenyl) -3- {6-[(dimethylamino) methyl] -5,6,7,8-tetrahydro-2-naphthalenyl} thieno [3,2-d] pyrimidine-4 (3H)- ON 2-[(dimethylaminomethyl) -2,3-dihydro-1,4-benzodioxin-6-amine to 6-[(dimethylamino) methyl] -5,6,7,8-tetrahydro-2-naphthalene The title compound was synthesized using the technique described in Example 16 instead of the amine (intermediate prepared according to WO 0121577) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39. (S, 1H), 7.98 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.24 (m , 3H), 2.9 (M, 1H), 2.82 (m, 2H), 2.43 (m, 2H), 2.2 (br, 6H), 1.96 (m, 2H), 1.36 (m, 2H) ES-LCMS m / z 450 (M + H).

6- (4-Chlorophenyl) -3- [6- (1-pyrrolidinylmethyl) -5,6,7,8-tetrahydro-2-naphthalenyl] thieno [3,2-d] pyrimidine-4 (3H) The title compound was synthesized using the technique described in Example 29, replacing -one dimethylamine with pyrrolidine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (s, 1H), 7.98 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.26 (m, 3H), 2.99 (m, 1H), 2.83 (m, 2H), 2.46 (m, 7H), 1.98 (m , 2H), 1.72 (m, 4H), 1.39 (m, 1H); ES-LCMS m / z 476 (M + H).

6- (4-Chlorophenyl) -3- [6- (1-piperidinylmethyl) -5,6,7,8-tetrahydro-2-naphthalenyl] thieno [3,2-d] pyrimidine-4 (3H) The title compound was synthesized using the technique described in Example 29, replacing the -one dimethylamine with piperidine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (s, 1H), 7.98 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.25 (m, 3H), 2.91 (m, 1H), 2.82 (m, 2H), 2.34 (m, 4H), 2.23 (d , J = 7.1 Hz, 2H), 1.97 (m, 2H), 1.53 (m, 4H), 1.40 (m, 4H); ES-LCMS m / z 490 (M + H).

3- [2- (Dimethylamino) -1-methyl-1H-benzimidazol-6-yl] -6- (4-nitrophenyl) thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: (2Z) -3-Chloro-3- (4-nitrophenyl) acrylonitrile
Starting from 1- (4-nitrophenyl) ethanone, as described in J. Prakt. Chem., 325, 915 (1983), (2Z) -3-chloro-3- (4-nitrophenyl) ) Acrylonitrile was prepared. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.3 (d, J = 9.2 Hz, 2H), 7.9 (d, J = 9.2 Hz, 2H), 6.2 (s, 1H).

Step B: methyl 3-amino-5- (4-nitrophenyl) thiophene-2-carboxylate methyl thioglycolate (0.517 g, 4.87 mmol) in methanol with sodium methoxide (0.26 g, 4.87 mmol) To a 10 mL solution was added at room temperature. 3-Chloro-3- (4-nitrophenyl) acrylonitrile (1.01 g, 4.87 mmol) from Step A was added and the resulting solution was heated to reflux for 10 minutes. The mixture was cooled to room temperature and filtered. The solid product was washed with water and dried in vacuo to give 0.846 g (62% yield) of a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 8.8 Hz, 2H), 7.18 (s, 1H), 6.67 (br s, 2H), 3.76 (s, 3H). ES-LCMS m / z = 278 (M ^<+> ).

Step C: methyl 3-{[(1E)-(dimethylamino) methylene] amino} -5- (4-nitrophenyl) thiophene-2-carboxylate as described in Example 1, Step D This compound was prepared from methyl 3-amino-5- (4-nitrophenyl) thiophene-2-carboxylate from Step B to give the desired intermediate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.2 (d, J = 8.8 Hz, 2H), 8.0 (d, J = 8.8 Hz, 2H), 7.9 (s, 1H), 7.6 (s, 1H), 3.7 (s, 3H), 3.0 (s, 3H), 2.95 (s, 3H). ES-LCMS m / z 333 (M ^<+> ).

Step D: 3- [2- (Dimethylamino) -1-methyl-1H-benzimidazol-6-yl] -6- (4-nitrophenyl) thieno [3,2-d] pyrimidine-4 (3H)- ON As described in Example 2, Step D, methyl 3-{[(1E)-(dimethylamino) methylene] amino} -5- (4-nitrophenyl) thiophene-2-carboxylate (previous step C) (0.200g, 0.60mmol) from ^{N 2, N 2,} 1- trimethyl -1H- benzimidazole-2,6-diamine (step D of example 1) (0.114g, 0.60mmol) The title compound was prepared by reacting with. The crude product was triturated with methanol to give 0.158 g (59% yield) of a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (s, 1H), 8.35 (d, J = 8.8 Hz, 2H), 8.23 (s, 1H), 8.21 (d, J = 8.8 Hz, 2H), 7.58 (m, 1H), 7.46 (m, 1H), 7.20 (m, 1H), 3.66 (s, 3H), 3.33 (s , 6H). ES-LCMS m / z 447 (M + H) ^<+> . The product is dissolved in dichloromethane, excess trifluoroacetic acid is added and the resulting solution is evaporated to dryness to give 3- [2- (dimethylamino) -1-methyl-1H-benzimidazol-6-yl]- 6- (4-Nitrophenyl) thieno [3,2-d] pyrimidin-4 (3H) -one was obtained as the trifluoroacetate salt. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (s, 1H), 8.33 (d, J = 8.8 Hz, 2H), 8.24 (s, 1H), 8.21 (d, J = 8.8 Hz, 2H), 7.92 (m, 1H), 7.51 (m, 1H), 7.49 (m, 1H), 3.80 (s, 3H), 3.27 (s , 6H).

6- (2-Chlorophenyl) -3- [2- (dimethylamino) -1-methyl-1H-benzimidazol-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: Methyl 5- (2-chlorophenyl) -3-{[(1E) -dimethylamino) methylidene] amino} -2-thiophenecarboxylate As described in Example 32, Steps A to C, 1 Starting from-(2-chlorophenyl) ethanone, methyl 5- (2-chlorophenyl) -3-{[(1E) -dimethylamino) methylidene] amino} -2-thiophenecarboxylate was prepared. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.8 (s, 1H), 7.7 (m, 1H), 7.6 (m, 1H), 7.4 (m, 2H), 7.2 (S, 1H), 3.7 (s, 3H), 3.0 (s, 3H), 2.95 (s, 3H). ES-LCMS m / z 323 (M + H).

Step B: 6- (2-Chlorophenyl) -3- [2- (dimethylamino) -1-methyl-1H-benzimidazol-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one Methyl 5- (2-chlorophenyl) -3-{[(1E) -dimethylamino) methylidene] amino} -2-thiophenecarboxylate (described above in Step A) as described in Example 2, Step D 0.311 g, 0.96 mmol) and N ² , N ² , 1-trimethyl-1H-benzimidazole-2,6-diamine (from Example 11, Step D) (0.183 g, 0.96 mmol) To give the title compound. The crude product was triturated with methanol and then suspended in dichloromethane and treated with excess trifluoroacetic acid. Diethyl ether was added and the precipitated trifluoroacetate salt was collected by filtration and dried in vacuo to give 0.185 g (35% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (s, 1H), 7.91 (s, 1H), 7.80 (s, 2H), 7.67 (m, 1H) 7.58 ( m, 1H), 7.52 (m, 3H), 3.80 (s, 3H), 3.28 (s, 6H), ES-LCMS m / z 436 (M + H).

6- (4-Chlorophenyl) -3- [6- (1-pyrrolidinylcarbonyl) -2-naphthalenyl] thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: 6- [6- (4-Chlorophenyl) -4-oxothieno [3,2-d] pyrimidin-3 (4H) -yl] -2-naphthalene carboxylic acid As described in Example 2, Step D Methyl 5- (4-chlorophenyl) -3-{([(1E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate (Example 1, Step D) (1.09 g, 3. The title compound was prepared by reacting 38 mmol) with 6-amino-2-naphthalenecarboxylic acid (0.63 g, 3.38 mmol) The crude product was triturated with methanol and dried in vacuo to turn off. white solid 0.345 g (25% ^{yield). 1 H NMR (400MHz, DMSO} -d 6) δ8.70 (s, 1H), 8.60 (s, 1H 8.28 (m, 1H), 8.23 (s, 1H), 8.09 (s, 2H), 8.03 (s, 1H), 7.96 (d, J = 8.6 Hz, 2H) ), 7.76 (m, 1H), 7.60 (d, J = 8.6 Hz, 2H).

Step B: 6- (4-Chlorophenyl) -3- [6- (1-pyrrolidinylcarbonyl) -2-naphthalenyl] thieno [3,2-d] pyrimidin-4 (3H) -one Oxalyl chloride (0. 015 mL, 0.17 mmol) and a catalytic amount of N, N-dimethylformamide was added to 6- [6- (4-chlorophenyl) -4-oxothieno [3,2-d] pyrimidin-3 (4H) -yl] -2. -Naphthalenecarboxylic acid (step A above) (0.050 g, 0.12 mmol) was added to a 2 mL suspension of dichloromethane. The reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo and the residue was suspended in 2 mL dichloromethane. Pyrrolidine (0.024 mL, 0.29 mmol) was added. The solvent was evaporated and the residue was purified by chromatography on silica gel using a 0 to 10% methanol gradient in dichloromethane to give 0.020 g (36% yield) of the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.57 (s, 1H), 8.21 (m, 2H), 8.17 (m, 1H), 8.05 (m, 1H), 8.01 (S, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.72 (m, 2H), 7.58 (d, J = 8.6 Hz, 2H), 3.52 (m , 2H), 3.46 (m, 2H), 1.90 (m, 2H), 1.83 (m, 2H). APCI-LCMS m / z 486 (M + H).

6- (4-Chlorophenyl) -3- [6- (1-piperidinylmethyl) -2-naphthalenyl] thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: Methyl 6-amino-2-naphthalenecarboxylate A mixture of 6-amino-2-naphthalenecarboxylic acid (5.00 g, 26.7 mmol), 10 mL concentrated sulfuric acid and 50 mL methanol was heated to reflux for 1.5 hours. The reaction mixture was cooled at room temperature, poured onto ice and then extracted with dichloromethane. The organic phase was dried over sodium sulfate and the solvent removed in vacuo to give 5.11 g (95% yield) of methyl 6-amino-2-naphthalenecarboxylate as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.36 (s, 1H), 7.79 (m, 2H), 7.57 (m, 1H), 7.05 (m, 1H), 6.86 (S, 1H), 5.88 (s, 2H), 3.88 (s, 3H).

Step B: (6-Amino-2-naphthalenyl) methanol While cooling in an ice bath, lithium aluminum hydride (41 mL of a 1.0 M solution in tetrahydrofuran) was added to methyl 6-amino-2-naphthalenecarboxylate (5. 11 g, 25.4 mmol) in 100 mL anhydrous tetrahydrofuran. The mixture was stirred at 5 ° C. for 2 hours and quenched with 5 mL of water. The mixture was filtered and the filter cake was washed with tetrahydrofuran (4 × 30 mL). The combined filtrates were dried and evaporated to give 4.06 g of a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.52 (m, 2H), 7.43 (m, 1H), 7.22 (m, 1H), 6.88 (m, 1H), 6.77 (S, 1H), 5.28 (s, 2H), 5.08 (m, 1H), 4.51 (m, 2H).

Step C: N- [6- (hydroxymethyl) -2-naphthalenyl] -2,2-dimethylpropanamide Triethylamine (1.2 mL: 8.67 mmol) was added to (6-amino-2-naphthalenyl) methanol (1.00 g). 5.78 mmol) in chloroform (60 mL). The mixture was cooled in an ice bath and pivaloyl chloride (0.81 mL, 10.4 mmol) was added. The reaction mixture was stirred at 0 ° C. for 1 hour. After warming to room temperature, the mixture was diluted with chloroform, washed with 1N aqueous hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with hexane: ethyl acetate to give 1.22 g (80% yield) of a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.26 (s, 1H), 7.78 (m, 3H), 7.47 (m, 3H), 4.83 (s, 2H), 1.66 (br s, 1H), 1.36 (s, 9H).

Step D: N- [6- (Chloromethyl) -2-naphthalenyl] -2,2-dimethylpropanamide 6.63 g (1.35 mmol / g, 8.95 mmol) polystyrene-triphenylphosphine resin, N- [6 A mixture of-(hydroxymethyl) -2-naphthalenyl] -2,2-dimethylpropanamide (1.15 g, 4.47 mmol) in 75 mL of carbon tetrachloride was heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature and filtered. The resin on the filter was washed with 4 × 20 mL of dichloromethane, the filtrates were combined and evaporated under reduced pressure to give 0.87 g (71% yield) of a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.80 (m, 4H), 7.46 (m, 2H), 7.23 and 7.05 (m, 1H), 4.74 (s, 2H), 1 .41 and 1.36 (s, 9H).

Step E: 2,2-Dimethyl-N- [6- (1-piperidinylmethyl) -2-naphthalenyl] propanamide N- [6- (Chloromethyl) -2-naphthalenyl] -2, from Step D A mixture consisting of 2-dimethylpropanamide (0.200 g, 0.73 mmol), piperidine (0.18 mL, 1.81 mmol) and 2 mL of tetrahydrofuran was heated to reflux for 1.5 hours. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel with dichloromethane: methanol to give 0.089 g (38% yield) of product as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (s, 1H), 7.80 (m, 2H), 7.75 (s, 1H), 7.52 (s, 1H), 7.48 (m , 2H), 3.65 (s, 2H), 2.47 (m, 4H), 1.65 (m, 4H), 1.48 (m, 2H), 1.40 (s, 9H).

Step F: 6- (1-Piperidinylmethyl) -2-naphthalenamine Aqueous hydrochloric acid (2 mL of 2N solution) was added to 2,2-dimethyl-N- [6- (1-piperidinylmethyl) from Step E above. ) -2-Naphthalenyl] propanamide (0.089 g, 0.27 mmol) was added to a 1 mL suspension of ethanol. The resulting solution was heated in the microwave at 110 ° C. for 40 minutes. The cooled reaction mixture was neutralized with solid sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over sodium sulfate and the solvent was evaporated, yielding 0.041 g (63% yield) of 6- (1-piperidinylmethyl) -2-naphthalenamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (m, 2H), 7.53 (m, 1H), 7.38 (m, 1H), 6.95 (m, 2H), 4.0 (br s, 2H), 3.61 (s, 2H), 2.46 (m, 4H), 1.61 (m, 4H), 1.44 (m, 2H).

Step F: 6- (4-Chlorophenyl) -3- [6- (1-piperidinylmethyl) -2-naphthalenyl] thieno [3,2-d] pyrimidin-4 (3H) -one Example 2, Step Methyl 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate (from Example 1, Step D) (as described in D) The title compound was prepared by reacting 0.055 g, 0.17 mmol) with 6- (1-piperidinylmethyl) -2-naphthalenamine (previously step E) (0.041 g, 0.17 mmol). did. The crude product was triturated with methanol to give 0.040 g (48% yield) of a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (s, 1H), 8.11 (s, 1H), 8.03 (m, 2H), 7.95 (m, 4H), 7.61 (M, 4H), 3.63 (s, 2H), 2.38 (m, 4H), 1.52 (m, 4H), 1.42 (m, 4H). Treatment with trifluoroacetic acid, as described in Example 31, Step B, gave 0.035 g of the corresponding salt. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 8.58 (s, 1H), 8.18 (m, 4H), 8.05 (s, 1H), 7.97 (M, 1H), 7.79 (m, 2H), 7.60 (m, 2H), 4.52 (s, 2H), 3.41 (m, 2H), 2.95 (m, 2H) 1.82 (m, 2H), 1.70 (m, 2H), 1.40 (m, 1H), 1.07 (m, 1H). ES-LCMS m / z 486 (M + H).

6- (4-Chlorophenyl) -3- (6-{[(3R) -3-hydroxy-1-pyrrolidinyl] methyl} -2-naphthalenyl) thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: 6- (4-Chlorophenyl) -3- [6- (hydroxymethyl) -2-naphthalenyl] thieno [3,2-d] pyrimidin-4 (3H) -one As described in Example 2, Step D. Methyl 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate (Example 1, Step D) (1.86 g, 5 The title compound was prepared by reacting .78 mmol) with (6-amino-2-naphthalenyl) methanol (Example 35, Step B) (1.00 g, 5.78 mmol). The crude product was purified by trituration with methanol to give 1.20 g of a beige powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.58 (s, 1H), 8.12 (s, 1H), 8.07 (m, 1H), 8.03 (s, 1H), 7.96 (M, 4H), 7.59 (m, 4H), 5.43 (m, 1H), 4.73 (m, 2H).

Step B: 6- [6- (4-Chlorophenyl) -4-oxothieno [3,2-d] pyrimidin-3 (4H) -yl] -2-naphthalenecarbaldehyde 6- (4-Chlorophenyl) from Step A -3- [6- (hydroxymethyl) -2-naphthalenyl] thieno [3,2-d] pyrimidin-4 (3H) -one (0.100 g, 0.24 mmol) and manganese dioxide (0.207 g, 2. 4 mmol) in chloroform (30 mL) was stirred at room temperature for 24 hours. The reaction mixture was filtered through celite and the solvent was evaporated in vacuo to give 0.091 g (87% yield) of a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.20 (s, 1H), 8.70 (s, 1H), 8.60 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.29 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.0 (m, 2H), 7.93 (d, J = 8.4 Hz, 2H) 7.83 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.6 Hz, 2H).

Step C: 6- (4-Chlorophenyl) -3- (6-{[(3R) -3-hydroxy-1-pyrrolidinyl] methyl} -2-naphthalenyl) thieno [3,2-d] pyrimidine-4 (3H ) -One sodium triacetoxyborohydride (0.117 g, 0.55 mmol), (3R) -3-pyrrolidinol (0.019 g, 0.22 mmol) and 6- [6- (4-chlorophenyl] from step B ) -4-oxothieno [3,2-d] pyrimidin-3 (4H) -yl] -2-naphthalenecarbaldehyde (0.091 g, 0.22 mmol) was added to a mixture in 10 mL of dichloroethane. The reaction mixture was stirred at room temperature for 20 hours, filtered and the filtrate was evaporated to dryness. The residue was purified by reverse phase HPLC on a _C18 column eluting with a 10 to 90% acetonitrile gradient in 0.1% formic acid to give 0.013 g (12% yield) of the title compound as the formate salt. It was. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (s, 1H), 8.13 (s, 1H), 8.08 (d, J = 2.11 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.99 (s, 1H), 7.94 (m, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.90 (m, 1H) 7.62 (dd, J = 9.0 Hz, 2.11 Hz, 1H), 7.57 (d, J = 8.6 Hz, 2H), 4.68 (br s, 1H), 4.17 (m , 1H), 3.73 (m, 2H), 2.72 (m, 1H), 2.59 (m, 1H), 2.45 (m, 1H), 2.33 (m, 1H), 1 .98 (m, 1H), 1.53 (m, 1H). ES-LCMS m / z 488 (M + H).

6- (4-Chlorophenyl) -3- {6-[(4-hydroxy-1-piperidinyl) methyl] -2-naphthalenyl} thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: N- (6-Formyl-2-naphthalenyl) -2,2-dimethylpropanamide Following the procedure in Example 36, Step B, N- [6- (hydroxymethyl) -2-naphthalenyl] -2,2 Reaction of dimethylpropanamide (Example 35, Step C) (0.310 g, 1.20 mmol) with manganese dioxide (1.04 g, 12.0 mmol) yields 0.285 g (93% yield) of the title compound. %)was gotten. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.12 (s, 1H), 8.37 (m, 1H), 8.27 (s, 1H), 7.96 (m, 2H), 7.92 (m , 1H), 7.56 (m, 2H), 1.38 (s, 9H). ES-LCMS m / z 256 (M + H).

Step B: N- {6-[(4-Hydroxy-1-piperidinyl) methyl] -2-naphthalenyl} -2,2-dimethylpropanamide As described in Example 36, Step C, N- ( 6-Formyl-2-naphthalenyl) -2,2-dimethylpropanamide (step A) (0.259 g, 1.01 mmol) and 4-hydroxypiperidine (0.102 g, 1.01 mmol) were triacetoxyborohydride. The title compound was prepared by reacting with sodium chloride. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (s, 1H), 7.75 (m, 2H), 7.78 (m, 1H), 7.45 (m, 3H), 3.71 (br s, 1H), 3.65 (m, 2H), 2.79 (m, 2H), 2.22 (m, 1H), 1.91 (m, 2H), 1.60 (m, 4H), 1.37 (s, 9H).

Step C: 1-[(6-Amino-2-naphthalenyl) methyl] -4-piperidinol According to the procedure in Example 35, Step F, N- {6-[(4-hydroxy-1-piperidinyl) methyl]- The title compound was obtained from 2-naphthalenyl} -2,2-dimethylpropanamide (step B above). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.62 (m, 1H), 7.57 (m, 2H), 7.36 (m, 1H), 6.97 (m, 1H), 6.94 (m , 1H), 3.82 (br s, 1H), 3.69 (br s, 2H), 3.60 (s, 2H), 2.79 (m, 2H), 2.18 (m, 2H) 1.89 (m, 2H), 1.61 (m, 2H).

Step D: 6- (4-Chlorophenyl) -3- {6-[(4-hydroxy-1-piperidinyl) methyl] -2-naphthalenyl} thieno [3,2-d] pyrimidin-4 (3H) -one Methyl 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate (Example 1, Step, as described in Example 2, Step D) D) (0.063 g, 0.195 mmol) and 1-[(6-amino-2-naphthalenyl) methyl] -4-piperidinol (previously step C) (0.050 g, 0.195 mmol) The title compound was prepared by The crude product was triturated with methanol / diethyl ether and then treated with trifluoroacetic acid as in Example 33 to give the corresponding salt, 0.030 g. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (br s, 1 H), 8.58 (s, 1 H), 8.22 (m, 1 H), 8.14 (m, 2 H), 8. 04 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.78 (m, 1H), 7.72 (m, 1H), 7.61 (d, J = 8. 6 Hz, 2H), 5.05 (m, 1H), 4.5 (m, 2H), 3.2 to 3.4 (m, 4H), 3.05 (m, 1H), 2.0 (m , 1H), 1.95 (m, 2H), 1.61 (m, 1H).

3- {2-[(Dimethylamino) methyl] -6-quinolinyl} -7- (4-fluorophenyl) -4 (3H) -quinazolinone

Step A: 2-Methyl-6-quinolinamine A catalytic amount of Pd / C was added to a solution of 2-methyl-6-nitroquinoline (4.0, 21.3 mmol) in 150 mL of ethyl alcohol. The mixture was stirred for 4 hours in a Parr hydrogenator under 2 atm hydrogen pressure. The mixture was filtered through celite. After removing the solvent under reduced pressure, 3.3 g of product was recovered as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83-7.78 (m, 2H); 7.17-7.10 (m, 2H); 6.87 (d, J = 2.8 Hz, 1H); 3.88 (bs, 2H); 2.66 (s, 3H). ES-LCMS m / z 159 (M + H).

Step B: 4-chloro-N- (2-methyl-6-quinolinyl) -2-nitrobenzamide 2-methyl-6-quinolinamine (3.3 g, 20.8 mmol), triethylamine (5.9 mL, 41.6 mmol) ) And 4-chloro-2-nitrobenzoyl chloride (5.0 g, 22.9 mmol) in DCM (60 mL) was stirred at room temperature for 3 hours. The mixture was diluted with DCM and washed with saturated sodium bicarbonate, water and brine. After drying over sodium sulfate, the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography eluting with 1% triethylamine with 10% acetone in DCM. The product was obtained as a tan solid (2.8 g). ¹ H NMR (400 MHz, d ₆ -DMSO) δ 10.98 (s, 1 H); 8.37 (s, 1 H); 8.28 (s, 1 H); 8.21 (d, J = 8.4 Hz, 7.98 (d, J = 8.4 Hz, 1H); 7.91-7.87 (m, 2H); 7.76 (d, J = 9.2 Hz, 2H); 7.38 (1H); d, J = 8.4 Hz, 1H); 3.31 (s, 3H). ES-LCMS m / z 342 (M + H).

Step C: 2-Amino-4-chloro-N- (2-methyl-6-quinolinyl) benzamide Boiling 4-chloro-N- (2-methyl-6-quinolinyl) -2-nitrobenzamide (500 mg, To a solution of 1.46 mmol) in ethyl alcohol (20 mL) was added tin chloride (988 mg, 4.39 mmol). The mixture was refluxed for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and then carefully washed several times with saturated Rochelle salt solution and then with brine. After drying, the solvent was removed and the product was recovered as a foam (295 mg). ES-LCMS m / z 312 (M + H).

Step D: 7-Chloro-3- (2-methyl-6-quinolinyl) -4 (3H) -quinazolinone 2-Amino-4-chloro-N- (2-methyl-6-quinolinyl) benzamide (295 mg, 0. (95 mmol) was dissolved in 5 mL of formic acid and heated to reflux for 2 hours. The formic acid was then removed under reduced pressure and the residue was dissolved in ethyl acetate. The resulting solution was washed with water, saturated sodium bicarbonate and brine. After removing the solvent under reduced pressure, the residue was purified by flash chromatography eluting with 10% acetone in DCM with 0.5% triethylamine. The product was obtained as an off-white solid (265 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J = 8.4 Hz, 1H); 8.22 (s, 1H); 8.18 (d, J = 8.4 Hz, 1H); 10 (d, J = 8.4 Hz, 1H); 7.84 (s, 1H); 7.79 (s, 1H); 7.70 (d, J = 8.8 Hz, 1H); 7.52 ( d, J = 8.4 Hz, 1H); 7.38 (d, J = 8.4 Hz, 1H); 2.79 (s, 3H). ES-LCMS m / z 322 (M + H).

Step E: 7-Chloro-3- (2-methyl-1-oxide-6-quinolinyl) -4 (3H) -quinazolinone 7-Chloro-3- (2-methyl-6-quinolinyl) -4 (3H)- To a solution of quinazolinone (530 mg, 1.65 mmol) in DCM (30 mL) was added m-CPBA (445 mg, 1.98 mmol). The mixture was heated to 40 ° C. and stirred at this temperature overnight. The precipitate was collected by filtration. The solid was washed with a small amount of saturated sodium bicarbonate solution. The product was recovered as a white solid (460 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.97 (d, J = 9.2 Hz, 1H); 8.31 (d, J = 8.4 Hz, 1H); 8.20 (s, 1H); 94 (s, 1H); 7.81-7.77 (m, 2H); 7.69 (d, J = 8.4 Hz, 2H); 7.54 (d, J = 8.4 Hz, 1H); 7.43 (d, J = 8.4 Hz, 1H); 2.76 (s, 3H). ES-LCMS m / z 338 (M + H).

Step F: 7-Chloro-3- [2- (chloromethyl) -6-quinolinyl] -4 (3H) -quinazolinone To a solution of p-toluenesulfonyl chloride (288 mg, 1.50 mmol) in 25 mL of dichloroethane, 7-chloro- 3- (2-Methyl-1-oxide-6-quinolinyl) -4 (3H) -quinazolinone (460 mg, 1.36 mmol) was added. The resulting mixture was heated to reflux for 40 hours. The solvent was removed under reduced pressure. The resulting residue was dissolved in DCM and washed with saturated sodium bicarbonate and brine. The solvent was removed under reduced pressure and the residue was purified by flash chromatography, eluting with 10% acetone in DCM with 1% triethylamine. The product was obtained as a white solid (235 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33-8.23 (m, 4H); 7.91 (s, 1H); 7.80-7.76 (m, 2H); 7.72 (d, J = 8.8 Hz, 1H); 7.53 (d, J = 8.4 Hz, 2H); 4.87 (s, 2H). ES-LCMS m / z 356 (M + H).

Step G: 7-chloro-3- {2-[(dimethylamino) methyl] -6-quinolinyl} -4 (3H) -quinazolinone 7-chloro-3- [2- (chloromethyl) -6-quinolinyl]- A mixture of 4 (3H) -quinazolinone (90 mg, 0.25 mmol) and excess dimethylamine (2M solution in methanol) was stirred overnight at room temperature. The reaction mixture was diluted with DCM and washed with water and brine. After drying, the solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with 10% acetone in DCM with 1% triethylamine. The product was obtained as a solid (76 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J = 8.4 Hz, 1H); 8.26-8.22 (m, 2H); 8.18 (d, J = 8.8 Hz, 1H) 7.86 (s, 1H); 7.79 (s, 1H); 7.74-7.65 (m, 2H); 7.52 (d, J = 8.4 Hz, 1H); 80 (s, 2H); 2.34 (s, 6H). ES-LCMS m / z 365 (M + H).

Step H: 3- {2-[(Dimethylamino) methyl] -6-quinolinyl} -7- (4-fluorophenyl) -4 (3H) -quinazolinone Under anhydrous conditions, 7-chloro-3- {2- [(Dimethylamino) methyl] -6-quinolinyl} -4 (3H) -quinazolinone (17 mg, 0.046 mmol), 4-fluorophenylboronic acid (13 mg, 0.093 mmol), potassium fluoride (8 mg, 0.14 mmol) ), Di-t-butylphosphinobiphenyl (6 mg, 0.14 mmol) and palladium acetate (3 mg, 0.01 mmol) were heated to 60 ° C. in 1 mL of THF for 2 hours. The mixture was filtered and the filtrate was diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with 10% acetone in DCM with 1% triethylamine. The title compound was obtained as a white solid (12.5 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (d, J = 8.4 Hz, 1H); 8.27-8.22 (m, 3H); 7.96 (s, 1H); 7.91 ( s, 1H); 7.79-7.68 (m, 5H); 7.23-7.19 (m, 2H); 3.94 (s, 2H); 2.46 (s, 6H). ES-LCMS m / z 425 (M + H).

7- (4-Chlorophenyl) -3- {2-[(dimethylamino) methyl] -6-quinolinyl} -4 (3H) -quinazolinone Example 38, replacing 4-fluorophenylboronic acid with 4-chlorophenylboronic acid The title compound was synthesized using the technique described in. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (d, J = 8.4 Hz, 1H); 8.37-8.25 (m, 3H); 7.99 (s, 1H); 7.98 ( s, 1H); 7.85 to 7.74 (m, 3H); 7.67 (d, J = 8.4 Hz, 1H); 7.50 (d, J = 8.4 Hz, 1H); 22 (bs, 2H); 2.72 (bs, 6H). ES-LCMS m / z 441 (M + H).

7- (4-Fluorophenyl) -3- [2- (1-pyrrolidinylmethyl) -6-quinolinyl] -4 (3H) -quinazolinone Use the technique described in Example 38, replacing dimethylamine with pyrrolidine. The title compound was synthesized. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48-8.44 (m, 2H); 8.38 (d, J = 8.0 Hz, 1H); 8.23 (d, J = 8.8 Hz, 1H) 8.16 (s, 1H); 7.99 (s, 1H); 7.95-7.89 (m, 2H); 7.85-7.81 (m, 2H); 7.72 ( d, J = 8.4 Hz, 1H); 7.27 (m, 2H); 4.30 (s, 2H); 2.99 (s, 4H); 1.99 (s, 4H). ES-LCMS m / z 451 (M + H).

6- (4-Chlorophenyl) -3- [2- (1-pyrrolidinylmethyl) -6-quinolinyl] thieno [3,2-d] pyrimidin-4 (3H) -one The technique described in Example 1 was used. Used to synthesize the title compound.

Step A: 6-Nitro-2- (1-pyrrolidinylmethyl) quinoline This intermediate was synthesized using the procedure described in Example 1, Step B, replacing dimethylamine with pyrrolidine. ¹ H NMR (400 MHz, CDCL3) δ 8.75 (d, J = 2.4 Hz, 1H); 8.43 (d, J = 9.2 Hz, 1H); 8.28 (d, J = 8.8 Hz, 8.18 (d, J = 9.6 Hz, 1H); 7.77 (d, J = 8.4 Hz, 1H); 3.99 (s, 2H); 2.64 to 2.61 (1H); s, 4H); 1.85 to 1.81 (m, 4H). ES-LCMS m / z 258 (M + H).

Step B: 2- (1-Pyrrolidinylmethyl) -6-quinolinamine This intermediate was synthesized using the procedure described in Example 1, Step C. ¹ H NMR (400 MHz, CDCL3) δ 7.87 (m, 2H); 7.49 (d, J = 8.4 Hz, 1H); 7.12 (d, J = 8.4 Hz, 1H); 6.88 (S, 1H); 3.92 (s, 2H); 3.92 (bs, 1H); 2.66 (bs, 4H); 1.84 to 1.80 (m, 4H). ES-LCMS m / z 228 (M + H).

Step C: 6- (4-Chlorophenyl) -3- [2- (1-pyrrolidinylmethyl) -6-quinolinyl] thieno [3,2-d] pyrimidin-4 (3H) -one 2-[(dimethyl The title compound was synthesized using the technique described in Example 1, Step E, replacing amino) methyl] -6-quinolinamine with 2- (1-pyrrolidinylmethyl) -6-quinolinamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 to 8.23 (m, 2H); 8.18 (d, J = 8.4 Hz, 1H); 7.88 (d, J = 2.4 Hz, 1H) ); 7.75-7.70 (m, 2H); 7.67 (d, J = 8.4 Hz, 2H); 7.56 (s, 1H); 7.45 (d, J = 8.8 Hz) ); 3.99 (s, 2H); 2.63 (bs, 4H); 1.85 to 1.82 (m, 4H). ES-LCMS m / z 473 (M + H).

6- (4-Chlorophenyl) -3- {2- (dimethylamino) -1- [2- (dimethylamino) ethyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 (3H) -one trifluoroacetate

Step A: N ′-(2-Bromo-5-nitrophenyl) -N, N-dimethylcarbamineimide (N- (dichloromethylidene) -N-methylmethanaminium chloride (1. 76 g, 10.8 mmol) and 2-bromo-5-nitroaniline (2.12 g, 9.79 mmol) were heated to reflux in methylene chloride (ca. 100 mL) for 16 hours. The reaction mixture was concentrated by rotary evaporation. The crude yellow solid was used without further purification.

Step B: N ′-(2-bromo-5-nitrophenyl) -N ″-[2- (dimethylamino) ethyl] -N, N-dimethylguanidine chloride N ′-(2-bromo-5-nitrophenyl) -N, N-dimethylcarbamic imido acid (Example 42, crude intermediate prepared in Step A: 600 mg, 1.9 mmol), triethylamine (272 μl, 0.727 mmol) and N, N-dimethyl-1,2- Ethanediamine (645 μl, 5.88 mmol) was heated to reflux in THF (ca. 50 mL) for 14 h The reaction mixture was diluted with water, basified with 1N NaOH and then extracted with ethyl acetate. dry the layer over MgSO _4, filtered, and concentrated to give the desired intermediate (690 mg, 1.9 mmol) was ^obtained. 1 H NMR (400 _{Hz, CDCl 3) δ2.2 (s} , 6H) 2.4 (m, 2H) 2.9 (s, 6H) 3.0 (m, 2H) 7.5 (dd, J = 8.6,2 .6 Hz, 1H) 7.6 (m, 2H) ES + = 358.28 and 360.19.

Step C: 1- [2- (Dimethylamino) ethyl] -N, N-dimethyl-5-nitro-1H-benzimidazol-2-amine (R)-(+)-2,2′-bis (diphenylphos Fino) -1,1′-binaphthyl (BINAP) (124 mg, 0.195 mmol) and cesium carbonate (899 mg, 2.77 mmol) were combined with N ′-(2-bromo-5-nitrophenyl) -N ″-[2 -(Dimethylamino) ethyl] -N, N-dimethylguanidine (Example 42, intermediate prepared in Step B, 395 mg, 0.06 mmol) is added to a solution of THF (ca. 25 mL). flushed _{.Pd (OAc) 2 (30mg,} 0.134mmol) was added, according to the reaction solution was heated at 75 ° C. 14 hours .HPLC, the reaction not Since a total reaction until complete, additional amounts of _{Pd (OAc) 2 (30mg,} 0.134mmol) and BINAP (124 mg, 0.195 mmol) was added (in this case, each of 1 The reaction was considered complete by HPLC after heating for an additional 24 hours at 75 ° C. The reaction was diluted with water and acidified with 1N HCl. The precipitate was filtered off and the filtrate was basified with 1N NaOH The mixture was extracted with ethyl acetate (2 ×) The organic layer was dried over MgSO ₄ , filtered and concentrated by rotary evaporation. was. the crude material was purified by silica gel chromatography (NH ₃ methanol 0-5% 2N in methylene chloride) to give the desired intermediate (165 mg, 0.60 mmol) was obtained _{^{1 H NMR (400MHz, CDCl 3}} ) δ2.3 (s, 6H) 2.7 (t, J = 7.6Hz, 2H) 3.1 (s, 6H) 4.2 (t, J = 7.4Hz , 2H) 7.2 (d, J = 8.8 Hz, 1H) 8.1 (dd, J = 8.8, 2.2 Hz, 1H) 8.4 (d, J = 2.2 Hz, 1H). ES + = 278.26.

Step D: 1- [2- (dimethylamino) ^ethyl] -N ^{2, N} 2 - dimethyl -1H- benzimidazole-2,5-diamine 1- [2- (dimethylamino) ethyl] -N, N-dimethyl A solution of -5-nitro-1H-benzimidazol-2-amine (Example 42, intermediate prepared in Step C, 110 mg, 0.38 mmol) in ethyl acetate (ca. 60 mL) is supported on carbon. Shake for 15 minutes on a Parr hydrogenator at 40 PSI with about 50 mg% Pd. The reaction was filtered and concentrated to give the desired intermediate (100 mg, 0.46 mmol).

Step E: 6- (4-Chlorophenyl) -3- {2- (dimethylamino) -1- [2- (dimethylamino) ethyl] -1H-benzimidazol-5-yl} thieno [3,2-d] Pyrimidine-4 (3H) -one trifluoroacetate 1- [2- (dimethylamino) ethyl] -N ² , N ² -dimethyl-1H-benzimidazole-2,5-diamineamine (Example 42, Step D) Intermediate (100 mg, 0.46 mmol) in methylene chloride was added to 1 g of phenol and 5- (4-chlorophenyl) -3-{[(E)-(dimethylamino) methylidene] amino} -2- To a test tube containing methyl thiophenecarboxylate (Example 1, intermediate prepared in Step D, 148 mg, 0.46 mmol). The reaction mixture was heated from room temperature to 180 ° C. for 30 minutes in an aluminum heat block. The reaction mixture was allowed to cool and then dissolved in methanol and absorbed onto silica. The product was purified by silica gel column chromatography (0-10% 2N NH ₃ methanol solution in methylene chloride). This compound was further purified by preparative HPLC chromatography (20% to 70% acetonitrile in water over 5 minutes) and then lyophilized to give the title compound as a white powder (25 mg, 0.05 mmol). Obtained. ¹ H NMR (400 MHz, DMSO-d6) δ 2.9 (s, 6H) 3.2 (s, 6H) 3.6 (t, J = 7.4 Hz, 2H) 4.6 (t, J = 7. 1 Hz, 2H) 7.5 (dd, J = 8.4, 1.9 Hz, 1H) 7.6 (d, J = 8.8 Hz, 2H) 7.7 (d, J = 2.1 Hz, 1H) 7.8 (d, J = 8.6 Hz, 1H) 7.9 (d, J = 8.6 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H) 10.2 (s, 1H). ES + = 493.4.

6- (4-Chlorophenyl) -3- {2- (dimethylamino) -1- [4- (methyloxy) phenyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 -(3H) -one methanesulfonate

Step A: N ′-(2-Bromo-5-nitrophenyl) -N, N-dimethyl-N ″-[4- (methyloxy) phenyl] guanidine N, N-dimethyl-N ′-[4- (methyl Oxy) phenyl] urea (0.50 g, 2.57 mmol), 2-bromo-5-nitroaniline (0.5 g, 2.3 mmol), POCl ₃ (360 μl, 3.86 mmol) and triethylamine (393 μl, 2.8 mmol) The solution in toluene (ca. 50 mL) was heated in toluene for 14 h at 110 ° C. The reaction mixture was concentrated by rotary evaporation, the solid was partially redissolved in ethyl acetate, water and 1 N NaOH. (pH> to 10) was added and filtered off solid material did not dissolve. the filtrate was extracted with ethyl acetate (3 ×), dried over MgSO _4, concentrated Was. This material Further purification by silica gel column chromatography (NH ₃ methanol in methylene chloride 0 to 10% 2N), the desired intermediate (475 mg, 1.21 mmol) was ^obtained. 1 H NMR (400 MHz, CDCl ₃ ) δ 3.0 (s, 6H) 3.7 (s, 3H) 6.7 (d, J = 9.0 Hz, 2H) 6.9 (d, J = 8.8 Hz, 2H) 7.5 (dd, J = 8.8, 2.6 Hz, 1H) 7.6 (d, J = 8.6 Hz, 1H) 7.7 (m, 1H) ES + = 393.16 and 395.18 .

Step B: 6- (4-Chlorophenyl) -3- {2- (dimethylamino) -1- [4- (methyloxyphenyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine -4 (3H) -one methanesulfonate N '-(2-bromo-5-nitrophenyl) -N, N-dimethyl using experimental procedures similar to Example 42, Steps C, D and E The title compound was prepared from —N ″-[4- (methyloxy) phenyl] guanidine (Example 43, intermediate prepared in Step A). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ2. 3 (s, 3H) 2.9 (s, 6H) 3.9 (s, 3H) 7.0 (d, J = 8.6 Hz, 1H) 7.2 (d, J = 8.8 Hz, 2H) 7.3 (m, 1H) 7.6 (m, 5H) 7.9 (d J = 8.6Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H) .ES + = 528.16.

6- (4-Chlorophenyl) -3- (2- (dimethylamino) -1-{[4- (methyloxy) phenyl] methyl} -1H-benzimidazol-5-yl) thieno [3,2-d] Pyrimidin-4 (3H) -one hydrochloride N, N-dimethyl-1,2-ethanediamine is replaced by 1- [4- (methyloxy) phenyl] -methanamine, detailed in Example 42, Steps B to E. The title compound was prepared using described methods. ¹ H NMR (400 MHz, DMSO-d6) δ 3.2 (s, 6H) 3.7 (s, 3H) 5.5 (s, 2H) 6.9 (d, J = 8.8 Hz, 2H) 2 (d, J = 8.6 Hz, 2H) 7.4 (m, 1H) 7.5 (m, 1H) 7.6 (d, J = 8.6 Hz, 2H) 7.7 (m, 1H) 7.9 (d, J = 8.6 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H). ES + = 542.25.

6- (4-Chlorophenyl) -3- (1-methyl-2,3-dihydro-1H-imidazo [1,2-a] benzimidazol-7-yl) thieno [3,2-d] pyrimidine-4 ( 3H) -On trifluoroacetate

Step A: {2- [5-Amino-2- (dimethylamino) -1H-benzimidazol-1-yl] ethyl} methylcarbamate 1,1-dimethylethyl Example 42, Step B (N, N-dimethyl- This intermediate was prepared using experimental procedures similar to Step C and Step D, substituting 1,2-ethanediamine for 1,1-dimethylethyl (2-aminoethyl) methylcarbamate). This intermediate was used without further purification.

Step B: Mixture of two products Using an experimental procedure similar to Example 42, Step E, {2- [5-amino-2- (dimethylamino) -1H-benzimidazol-1-yl] Ethyl} -methylcarbamate 1,1-dimethylethyl (Example 45, intermediate prepared in Step A, 94 mg, 0.30 mmol) and 5- (4-chlorophenyl) -3-{[(E)-(dimethyl Amino) methylidene] amino} -2-thiophenecarboxylate methyl (Example 1, intermediate prepared in Step D, 100 mg, 0.31 mmol) was combined to give two compounds.

Example 45, Step B, Product 1: (6- (4-Chlorophenyl) -3- (1-methyl-2,3-dihydro-1H-imidazo [1,2-a] benzimidazol-7-yl) Thieno [3,2-d] pyrimidine-4 (3H) -one trifluoroacetate)
The title compound was isolated by preparative HPLC (6 mg, 0.012 mmol). ¹ H NMR (400 MHz, DMSO-d6) δ 3.1 (s, 3H) 4.2 (m, 2H) 4.3 (m, 2H) 7.3 (m, 1H) 7.5 (m, 1H) 7.6 (d, J = 8.6 Hz, 2H) 7.6 (m, 1H) 7.9 (d, J = 8.4 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H). ES + = 434.15.

  Example 45, Step B, Product 2: {2- [5- [6- (4-Chlorophenyl) -4-oxothieno [3.2-d] pyrimidin-3 (4H) -yl] -2- (dimethyl Amino) -1H-benzimidazol-1-yl] ethyl} methylcarbamate 1,1-dimethylethyl. About 5 mg of this intermediate was used in Example 46.

6- (4-Chlorophenyl) -3- {2- (dimethylamino) -1- [2- (methylamino) ethyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 (3H) -one trifluoroacetate {2- [5- [6- (4-chlorophenyl) -4-oxothieno [3.2-d] pyrimidin-3 (4H) -yl] -2- (dimethylamino) -1H-Benzimidazol-1-yl] ethyl} methylcarbamate 1,1-dimethylethyl (Example 45, Step B product 2, 5 mg) was dissolved in 1 mL of methylene chloride and 1 mL of TFA. After 30 minutes, the reaction was concentrated to give 3 mg of the title compound. ¹ H NMR (400 MHz, DMSO-d6) δ 2.7 (t, J = 5.2 Hz, 2H) 3.2 (s, 6H) 3.4 (m, 2H) 4.5 (t, J = 7. 4 Hz, 2H) 7.5 (m, 1H) 7.6 (d, J = 8.6 Hz, 2H) 7.7 (d, J = 1.9 Hz, 1H) 7.7 (d, J = 8. 8 Hz, 1H) 7.9 (d, J = 8.6 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H) 8.7 (s, 2H). ES + = 479.25.

6- (4-Chlorophenyl) -3- {2- (dimethylamino) -1- (2-piperidinylmethyl) -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 ( 3H) -one trifluoroacetate salt Example 42, Step B (N, N-dimethyl-1,2-ethanediamine is replaced with 1,1-dimethylethyl 2- (aminomethyl) -1-piperidinecarboxylate), The title compound was prepared using the same experimental procedure as Example 42, Steps C to E and the amine protection used in Example 46. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.6 (m, 6H) 3.0 (s, 6H) 4.4 (m, 2H) 7.3 (m, 1H) 7.6 (m, 4H 7.9 (d, J = 8.8 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H) 8.5 (m, 1H) 8.7 (m, 1H). ES + = 519.21.

3- [1- (2-Aminoethyl) -2- (dimethylamino) -1H-benzimidazol-5-yl] -6- (4-chlorophenyl) thieno [3,2-d] pyrimidine-4 (3H) -Ontrifluoroacetate salt Example 42, Step B (N, N-dimethyl-1,2-ethanediamine is replaced with 1,1-dimethylethyl 2- (aminomethyl) carbamate), Example 42, Step C The title compound was prepared using the same experimental procedure as for E and the amine protection used in Example 46. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ2.9 (s, 6H) 3.2 (t, J = 7.3 Hz, 1H) 4.3 (t, J = 7.9 Hz, 2H) 7.2 (Dd, J = 8.2, 1.8 Hz, 1H) 7.5 (d, J = 8.4 Hz, 1H) 7.6 (d, J = 2.2 Hz, 1H) 7.6 (m, 2H ) 7.9 (m, 4H) 8.0 (s, 1H) 8.4 (s, 1H). ES + = 465.08.

3- [1- {2- [Bis (1-methylethyl) amino] ethyl} -2- (dimethylamino) -1H-benzimidazol-5-yl] -6- (4-chlorophenyl) thieno [3,2 -D] pyrimidine-4 (3H) -hydrochloride Example 42, Step B (N, N-dimethyl-1,2-ethanediamine was converted to N, N-bis (1-methylethyl) -1,2-ethanediamine The title compound was prepared using an experimental procedure similar to Example 42, steps C to E. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.3 (d, J = 6.4 Hz, 6H) 1.4 (d, J = 6.6 Hz, 6H) 3.2 (s. Br, 6H) 3 .4 (m, 2H) 3.8 (m, 2H) 4.8 (m, 2H) 7.4 (m, 1H) 7.6 (d, J = 8.8 Hz, 2H) 7.7 (m , 1H) 7.8 (m, 1H) 7.9 (d, J = 8.8 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H). ES + = 548.78.

6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1- (3-morpholin-4-ylpropyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidine- 4 (3H) -one trifluoroacetate

Step A: 3-[(2,4-Dinitrophenyl) amino] propan-1-ol A solution of 3-amino-1-propanol (7.86 mL, 103 mmol) in ethanol (30 mL) was added to triethylamine (14.3 mL, 103 mmol). ) Followed by the dropwise addition of 2,4-dinitrofluorobenzene (8.6 mL, 69 mmol). The reaction mixture was stirred for 1 hour and then heated in a sealed tube at 80 ° C. overnight. Concentration followed by column chromatography on silica gel using methylene chloride gave 3-[(2,4-dinitrophenyl) amino] propan-1-ol as a yellow solid (14.3 g, 86%) Obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.8 (m, 2H) 3.6 (m, 4H) 4.8 (s, 1H) 7.2 (d, J = 9.7 Hz, 1H) 8 .3 (ddd, J = 9.7, 2.8, 0.8 Hz, 1H) 8.9 (d, J = 2.8 Hz, 1H) 9.1 (m, 1H).

Step B: 3-[(2-Amino-4-nitrophenyl) amino] propan-1-ol Sodium dithionite (28.9 g, 166 mmol) in water (100 mL) was added to 3-[(2,4 -Dinitrophenyl) amino] propan-1-ol (Example 50, intermediate prepared in Step A, 10.0 g, 41.5 mmol) in ethanol: dioxane (160: 160 mL) solution slowly at 40 ° C. added. The reaction mixture was warmed to 80 ° C., stirred for 90 minutes and then cooled to room temperature. The solid was filtered and the solution was concentrated. The residue was taken up in water and washed with dichloromethane. The combined organics were dried and the solvent removed in vacuo. The residue was recrystallized from methanol: dichloromethane to give 3-[(2-amino-4-nitrophenyl) amino] propan-1-ol as a brown solid (3.11 g, 36% yield). It was. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.7 (m, 2H) 3.2 (m, 2H) 3.5 (m, 2H) 4.5 (m, 1H) 5.1 (m, 2H ) 5.9 (m, 1H) 6.5 (d, J = 9.0 Hz, 1H) 7.4 (dd, J = 2.8 Hz, 1H) 7.5 (dd, J = 8.8, 2) .6Hz, 1H).

Step C: 1- (3-Chloropropyl) -N, N-dimethyl-5-nitro-1H-benzimidazol-2-amine Iminium phosgene (693 mg, 4.27 mmol) was added to triethylamine (792 μL, 5 .68 mmol) and 3-[(2-amino-4-nitrophenyl) amino] propan-1-ol (Example 50, intermediate prepared in Step B, 300 mg, 1.42 mmol) in dichloroethane (18 mL) To the solution was added at 80 ° C. The reaction mixture was stirred at reflux for 25 minutes, cooled to room temperature and quenched with methanol. The reaction was diluted with dichloromethane, washed with brine, dried and concentrated. The residue was purified on silica gel (0-8% MeOH / CH ₂ Cl ₂ ) to give 1- (3-chloropropyl) -N, N-dimethyl-5-nitro-1H-benzimidazol-2-amine as a tan color. As a solid (250 mg, 62% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.3 (m, 2H) 3.1 (m, 6H) 3.5 (t, J = 5.9 Hz, 2H) 4.3 (m, 2H) 7.2 (D, J = 8.8 Hz, 1H) 8.1 (dd, J = 8.8, 2.2 Hz, 1H) 8.4 (d, J = 2.1 Hz, 1H). LCMS m / z = 283 (m + H ^< + ^> ).

Step D: N, N-dimethyl-1- (3-morpholin-4-ylpropyl) -5-nitro-1H-benzimidazol-2-amine 1- (3-chloropropyl) -N, N-dimethyl-5 -A solution of nitro-1H-benzimidazol-2-amine (Example 50, intermediate prepared in Step C, 122 mg, 0.432 mmol) in THF (6 mL) with excess morpholine followed by excess potassium carbonate. Processed. The reaction was heated in a sealed tube at 90 ° C. for 2 days. The reaction mixture was cooled to room temperature, concentrated, dissolved in dichloromethane, washed with brine and extracted with dichloromethane. The combined organics were dried and chromatographed on silica gel (2.0N NH ₃ / CH ₂ Cl _{2 in} 0-5% MeOH) to give N, N-dimethyl-1- (3-morpholin-4-yl. Propyl) -5-nitro-1H-benzimidazol-2-amine was obtained as a yellow oil (142 mg, 98% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.0 (m, 2H) 2.3 (t, J = 6.6 Hz, 2H) 2.3 (m, 4H) 3.0 (m, 6H) 3.7 (M, 4H) 4.2 (t, J = 7.2 Hz, 2H) 7.2 (d, J = 8.8 Hz, 1H) 8.0 (dd, J = 8.8, 2.2 Hz, 1H 8.4 (d, J = 2.2 Hz, 1H). LCMS m / z = 334 (m + H ^< + ^> ).

Step E: 6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1- (3-morpholin-4-ylpropyl) -1H-benzimidazol-5-yl] thieno [3,2-d Pyrimidine-4 (3H) -one trifluoroacetate salt N, N-dimethyl-1- (3-morpholin-4-ylpropyl) -5-nitro-1H-benzimidazol-2-amine in ethanol (Examples) 50, intermediate prepared in Step D, 152 mg, 0.456 mmol) was treated with a catalytic amount of Pd / C (10%) and stirred under hydrogen gas (40 psi) for 1 hour. The reaction mixture was filtered through celite and concentrated. The crude material was prepared in methyl 5- (4-chlorophenyl) -3-{[(E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate (Example 1, Step D) in phenol (1 mL). Intermediate 155 mg, 0.479 mmol) and dichloromethane (4 mL), warmed to 130 ° C. and stirred for about 30 min. The reaction was cooled and purified on silica gel (2.0-5% NH ₃ / CH ₂ Cl _{2 in} 0-5% MeOH). The compound is dissolved in dichloromethane, treated with 2 equivalents of trifluoroacetic acid and concentrated to give 6- (4-chlorophenyl) -3- [2- (dimethylamino) -1- (3-morpholin-4-ylpropyl)- 231 mg of 1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetate (title compound) was obtained as a white solid. ¹ H NMR (TFA, 300 MHz, DMSO-d ₆ ) δ 2.2 (m, 2H) 3.1 (m, 2H) 3.2 (m, 6H) 3.3 (m, 2H) 3.4 (m , 2H) 3.6 (m, 2H) 4.0 (m, 2H) 4.3 (t, J = 8.6 Hz, 2H) 7.4 (d, J = 8.0 Hz, 1H) 7.6 (Dt, J = 8.6, 2.8 Hz, 2H) 7.7 (d, J = 1.7 Hz, 1H) 7.7 (d, J = 8.6 Hz, 1H) 7.9 (dt, J = 8.8, 2.5 Hz, 2H) 8.4 (s, 1H) 9.9 (bs, 1H). APCI-LCMS m / z = 549 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1- (3-piperidin-1-ylpropyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidine- 4 (3H) -one trifluoroacetate The title compound was synthesized using the techniques described in Example 50, Steps D and E, replacing morpholine with piperazine. ¹ H NMR (TFA salt, 300 MHz, DMSO-d ₆ ) δ 1.4 (m, 1H) 1.6 (m, 3H) 1.8 (m, 2H) 2.2 (m, 2H) 2.9 ( m, 2H) 3.1 (m, 6H) 3.2 (m, 2H) 3.4 (m, 2H) 4.3 (m, 2H) 7.4 (d, J = 8.3 Hz, 1H) 7.6 (m, 2H) 7.6 (d, J = 1.9 Hz, 1H) 7.7 (d, J = 8.3 Hz, 1H) 7.9 (s, 2H) 8.0 (m, 1H) 8.4 (s, 1H) 9.2 (bs, 1H). APCI-LCMS m / z = 547 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1- (3-pyrrolidin-1-ylpropyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidine- 4 (3H) -one trifluoroacetate The title compound was synthesized using the techniques described in Example 50, Steps D and E, replacing morpholine with pyrrolidine. ¹ H NMR (TFA salt, 400 MHz, DMSO-d ₆ ) δ 1.9 (m, 2H) 2.0 (m, 2H) 2.2 (m, 2H) 3.0 (m, 2H) 3.2 ( m, 6H) 3.3 (m, 2H) 3.5 (m, 2H) 4.3 (t, J = 7.4 Hz, 2H) 7.4 (d, J = 9.1 Hz, 1H) 6 (dt, J = 8.6, 1.9 Hz, 2H) 7.7 (d, J = 1.9 Hz, 1H) 7.7 (d, J = 8.4 Hz, 1H) 7.9 (dt, J = 8.8, 2.1 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H) 9.9 (bs, 1H). APCI-LCMS m / z = 533 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- (2- (dimethylamino) -1- {3- [ethyl (methyl) amino] propyl} -1H-benzimidazol-5-yl) thieno [3,2-d] Pyrimidine-4 (3H) -one trifluoroacetate The title compound was synthesized using the techniques described in Example 50, Steps D and E, replacing morpholine with N-ethylmethylamine. ¹ H NMR (TFA salt, 400 MHz, DMSO-d ₆ ) δ 1.2 (t, J = 7.2 Hz, 3H) 2.1 (m, 2H) 2.7 (d, J = 5.0 Hz, 3H) 3.1 (m, 2H) 3.2 (s, 6H) 3.2 (m, 2H) 4.3 (t, J = 7.9 Hz, 2H) 7.4 (d, J = 7.2 Hz, 1H) 7.6 (dt, J = 8.8, 2.2 Hz, 2H) 7.6 (d, J = 1.7 Hz, 1H) 7.7 (d, J = 8.1 Hz, 1H) 9 (dt, J = 8.8, 2.1 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H) 9.4 (bs, 1H). APCI-LCMS m / z = 521 (m + H ^< + ^> ).

{3- [5- [6- (4-Chlorophenyl) -4-oxothieno [3,2-d] pyrimidin-3 (4H) -yl] -2- (dimethylamino) -1H-benzimidazol-1-yl ] Propyl} t-butyl methylcarbamate

Step A: N, N-dimethyl-1- [3- (methylamino) propyl] -5-nitro-1H-benzimidazol-2-amine The technique described in Example 50, Step D, substituting morpholine for methylamine. Was used to synthesize the title compound. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.0 (m, 2H) 2.4 (s, 3H) 2.6 (t, J = 6.6 Hz, 2H) 3.1 (s, 6H) 4.2 (M, 2H) 7.3 (d, J = 8.8 Hz, 1H) 8.1 (dd, J = 8.8, 2.2 Hz, 1H) 8.4 (d, J = 2.2 Hz, 1H) ). APCI-LCMS m / z = 278 (m + H ^< + ^> ).

Step B: t-butyl {3- [5-amino-2- (dimethylamino) -1H-benzimidazol-1-yl] propyl} methylcarbamate N, N-dimethyl-1- [3- (methyl Amino) propyl] -5-nitro-1H-benzimidazol-2-amine (Example 54, intermediate prepared in Step A, 87 mg, 0.31 mmol) was treated with a catalytic amount of Pd / C (10%). And stirred for 1 hour under hydrogen gas (40 psi). The reaction mixture was filtered through celite and concentrated. This crude material was taken up in dichloromethane and treated with di-t-butyl dicarbonate (69 mg, 0.31 mmol). The reaction mixture was stirred for 1 h and then purified on silica gel (0-10% 2N NH _{3 in} MeOH / CH ₂ Cl ₂ ) to give the title compound (50 mg, 46% yield). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.5 (s, 9H) 2.0 (m, 2H) 2.8 (s, 3H) 3.0 (s, 6H) 3.3 (m, 2H) 3 .6 (m, 2H) 4.0 (m, 2H) 6.6 (dd, J = 8.3, 2.2 Hz, 1H) 6.9 (m, 2H). APCI-LCMS m / z = 348 (m + H ^< + ^> ).

Step C: {3- [5- [6- (4-Chlorophenyl) -4-oxothieno [3,2-d] pyrimidin-3 (4H) -yl] -2- (dimethylamino) -1H-benzimidazole- 1-yl] propyl} methylcarbamate t-butyl {3- [5-amino-2- (dimethylamino) -1H-benzimidazol-1-yl] propyl} methylcarbamic acid in phenol (1 mL) and dichloromethane (5 mL) A solution consisting of t-butyl (Example 54, intermediate prepared in Step B, 50 mg, 0.14 mmol) was treated with the intermediate prepared in Example 1, Step D (51 mg, 0.16 mmol). , Heated to 100 ° C. and heated for 30 minutes. The reaction was cooled and purified on silica gel (0-10% 2N NH _{3 in} MeOH / CH ₂ Cl ₂ ) to give the title compound as a white solid (29 mg). ¹ H NMR (TFA salt, 400 MHz, CDCl ₃ ) δ 1.5 (s, 9H) 2.1 (m, 2H) 2.9 (m, J = 17.8 Hz, 3H) 3.1 (s, 6H) 3.3 (s, 2H) 4.1 (t, J = 7.9 Hz, 2H) 7.2 (d, J = 7.9 Hz, 1H) 7.3 (d, J = 8.4 Hz, 1H) 7.4 (dt, J = 8.6, 2.1 Hz, 2H) 7.5 (s, 1H) 7.6 (m, 1H) 7.7 (dt, J = 8.6, 1.9 Hz, 2H) 8.2 (s, 1H). ES-LCMS m / z = 593 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- {2- (dimethylamino) -1- [3- (methylamino) propyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 (3H) -one trifluoroacetate The compound obtained in Example 54, Step D (25 mg, 0.042 mmol) was dissolved in methanol and treated with methanesulfonic acid (11 μL, 0.17 mmol). The reaction was stirred overnight and purified by preparative HPLC to give the title compound as a white solid (15 mg). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.1 (m, 2H) 2.6 (m, 3H) 3.0 (t, J = 7.7 Hz, 2H) 3.2 (s, 6H) 4 .3 (t, J = 6.9 Hz, 2H) 7.4 (dd, J = 8.0, 1.7 Hz, 1H) 7.6 (dt, J = 8.6, 1.9 Hz, 2H) 7 .6 (d, J = 1.9 Hz, 1H) 7.7 (d, J = 8.6 Hz, 1H) 7.9 (dt, J = 8.8, 2.2 Hz, 2H) 8.0 (s , 1H) 8.4 (s, 1H). APCI-LCMS m / z = 593 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1- (3-methoxypropyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidine-4 (3H) -Methanesulfonate

Step A: 1- (3-Methoxypropyl) -N, N-dimethyl-5-nitro-1H-benzimidazol-2-amine The intermediate obtained in Example 50, Step C (110 mg, 0.393 mmol) Dissolved in methanol, treated with sodium hydride (60%, 18 mg, 0.43 mmol) and stirred at 80 ° C. overnight. According to TLC, no starting material was consumed. Subsequently, potassium carbonate was added, and the reaction solution was stirred at 80 ° C. for 1 day. The reaction was filtered, concentrated, diluted with dichloromethane and washed with water. The organic layer was dried, concentrated and the residue was purified using silica gel (ethyl acetate 0-100% / hexanes) to give the title compound as a yellow oil (75 mg, 69% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.1 (m, 2H) 3.1 (s, 6H) 3.3 (t, 3H) 3.3 (t, J = 5.5 Hz, 2H) 3.5 (S, 1H) 4.2 (m, 2H) 7.2 (d, J = 8.8 Hz, 1H) 8.0 (dd, J = 2.2 Hz, 1H) 8.4 (d, J = 2) .1Hz, 1H). APCI-LCMS m / z = 279 (m + H ^< + ^> ).

Step B: 6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1- (3-methoxypropyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidine-4 (3H) -Onmethanesulfonate N, N-dimethyl-1- (3-morpholin-4-ylpropyl) -5-nitro-1H-benzimidazol-2-amine is converted to 1- (3-methoxypropyl)- The title compound was synthesized using the technique described in Example 50, Step E, instead of N, N-dimethyl-5-nitro-1H-benzimidazol-2-amine. ¹ H NMR (MsOH salt, 300 MHz, DMSO-d ₆ ) δ2.1 (m, 2H) 2.3 (s, 3H) 3.3 (s, 6H) 3.4 (t, J = 5.7 Hz, 2H) 4.4 (t, J = 6.6 Hz, 2H) 7.5 (dd, J = 8.6, 1.9 Hz, 1H) 7.6 (dt, J = 8.6, 1.9 Hz, 2H) 7.7 (d, J = 1.9 Hz, 1H) 7.8 (d, J = 8.6 Hz, 1H) 8.0 (td, J = 8.6, 1.9 Hz, 2H) 8. 0 (s, 1H) 8.5 (s, 1H). ES-LCMS m / z = 494 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- (1-methyl-1,2,3,4-tetrahydropyrimido [1,2-a] benzimidazol-8-yl) thieno [3,2-d] pyrimidine- 4 (3H) -Onmethanesulfonate N, N-dimethyl-1- (3-morpholin-4-ylpropyl) -5-nitro-1H-benzimidazol-2-amine is converted to 1- (3-chloropropyl) Instead of -N, N-dimethyl-5-nitro-1H-benzimidazol-2-amine (Example 50, intermediate prepared in Step C), using the technique described in Example 50, Step E The title compound was synthesized. ¹ H NMR (MsOH salt, 400 MHz, DMSO-d ₆ ) δ 2.2 (m, 2H) 2.3 (s, 3H) 3.2 (s, 3H) 3.6 (t, J = 5.2 Hz, 2H) 4.1 (t, J = 6.0 Hz, 2H) 7.5 (dd, J = 8.4, 1.9 Hz, 1H) 7.6 (dt, J = 8.6, 2.1 Hz, 2H) 7.6 (d, J = 8.6 Hz, 1H) 7.7 (d, J = 1.9 Hz, 1H) 7.9 (dt, J = 8.6, 2.1 Hz, 2H) 8. 0 (s, 1H) 8.4 (s, 1H). ES-LCMS m / z = 448 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- (1- {3- [ethyl (methyl) amino] propyl} -2-methyl-1H-benzimidazol-5-yl) thieno [3,2-d] pyrimidine-4 (3H) -trifluoroacetate

Step A: 3- (2-Methyl-5-nitro-1H-benzimidazol-1-yl) propan-1-ol of the intermediate obtained in Example 50, Step B (3.87 g, 18.3 mmol) The warm dimethylacetamide solution was treated with acetyl chloride (5.18 mL, 73.2 mmol) and stirred for 2 hours. Concentrated aqueous hydrochloric acid (4 mL) was added, then the reaction mixture was heated to 100 ° C. and stirred for 2 hours. The reaction was cooled to room temperature, neutralized using 10N sodium hydroxide, diluted with water and extracted with ethyl acetate. The combined organics were dried and purified using silica gel (0-10% methanol / dichloromethane). Due to the small amount of impurities, the resulting solid was recrystallized to give a tan solid (1.74 g, 40% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ1.9 (m, 2H) 2.6 (s, 3H) 3.4 (q, J = 4.8 Hz, 2H) 4.3 (t, J = 7 .1 Hz, 2H) 4.7 (t, J = 4.9 Hz, 1H) 7.7 (d, J = 9.0 Hz, 1H) 8.1 (dd, J = 9.0, 2.2 Hz, 1H) 8.4 (d, J = 2.1 Hz, 1H). ES-LCMS m / z = 236 (m + H ^< + ^> ).

Step B: 3- (2-Methyl-5-nitro-1H-benzimidazol-1-yl) propyl 4-methylbenzenesulfonate Example 58, intermediate (686 mg, 2.92 mmol) obtained in Step A A solution of warm tetrahydrofuran (45 mL) was treated with tosyl chloride (1.22 g, 6.42 mmol) followed by sodium hydride (60% dispersion, 234 mg, 5.84 mmol) and stirred at 50 ° C. for 3 hours. The reaction was then concentrated, diluted with dichloromethane and washed with water. The organic layer was dried and concentrated. The residue was recrystallized from dichloromethane and ethyl acetate and filtered to give the title compound as a white solid (1.06 g, 93% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.0 (m, 2H) 2.4 (s, 3H) 2.5 (s, 3H) 4.1 (t, J = 6.0 Hz, 2H) 4 .3 (t, J = 6.9 Hz, 2H) 7.4 (d, J = 7.9 Hz, 2H) 7.6 (d, J = 9.0 Hz, 1H) 7.7 (dt, J = 8 .5, 2.0 Hz, 2H) 8.1 (dd, J = 8.8, 2.2 Hz, 1H) 8.4 (d, J = 2.2 Hz, 1H). ES-LCMS m / z = 390 (m + H ^< + ^> ).

Step C: N-ethyl-N-methyl-3- (2-methyl-5-nitro-1H-benzimidazol-1-yl) -1-propanamine Intermediate (124 mg) obtained in Example 58, Step B , 0.318 mmol) in warm THF (4 mL), treated with N-ethylmethylamine (1 mL), and then potassium carbonate (88 mg, 0.64 mmol) was added. The reaction mixture was heated to 80 ° C. in a sealed tube and stirred overnight. After cooling, the reaction mixture was filtered, concentrated and purified on silica gel (0-10% 2.0N NH _{3 in} MeOH / CH ₂ Cl ₂ ) to give the title compound as a white solid (71 mg). It was. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.9 (t, J = 7.2 Hz, 3H) 1.9 (m, 2H) 2.1 (s, 3H) 2.2 (m, 4H) 2 .6 (s, 3H) 4.3 (t, J = 7.1 Hz, 2H) 7.7 (d, J = 9.0 Hz, 1H) 8.1 (dd, J = 8.8, 2.2 Hz) , 1H) 8.4 (d, J = 2.2 Hz, 1H). ES-LCMS m / z = 277 (m + H ^< + ^> ).

Step D: 6- (4-Chlorophenyl) -3- (1- {3- [ethyl (methyl) amino] propyl} -2-methyl-1H-benzimidazol-5-yl) thieno [3,2-d] Pyrimidine-4 (3H) -one trifluoroacetate N, N-dimethyl-1- (3-morpholin-4-ylpropyl) -5-nitro-1H-benzimidazol-2-amine was prepared in Example 58, Step C. The title compound was synthesized using the technique described in Example 50, Step E, in place of the intermediate obtained in. ¹ H NMR (TFA salt, 400 MHz, CDCl ₃ ) δ 1.3 (t, J = 7.2 Hz, 3H) 2.4 (m, 2H) 2.6 (s, 3H) 2.8 (bs, 3H) 2.8 (m, 2H) 3.0 (m, 1H) 3.2 (m, 2H) 3.4 (m, 1H) 4.5 (m, 2H) 7.4 (dt, J = 8. 9, 2.2 Hz, 2H) 7.5 (m, 2H) 7.6 (dt, J = 8.8, 2.4 Hz, 2H) 7.9 (m, 2H) 8.1 (s, 1H) 12.0 (bs, 2H). ES-LCMS m / z = 492 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- {2-methyl-1- [3- (1-pyrrolidinyl) propyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 (3H ) -Onmethanesulfonate The title compound was synthesized using the techniques described in Example 58, Step C and Example 50, Step E, replacing N-ethylmethylamine with pyrrolidine. ¹ H NMR (MsOH salt, 400 MHz, DMSO-d ₆ ) δ 1.8 (m, 2H) 2.0 (m, 2H) 2.2 (m, 2H), 2.3 (s, 3H) 2.8 (S, 3H) 3.0 (m, 2H) 3.3 (m, 2H) 3.5 (m, 2H) 7.6 (dt, J = 8.8, 2.1 Hz, 2H) 7.7 (D, J = 8.6 Hz, 1H) 7.9 (dt, J = 8.8, 2.1 Hz, 2H) 8.0 (s, 1H) 8.1 (m, 2H) 8.5 (s , 1H) 9.6 (bs, 1H). APCI-LCMS m / z = 505 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- {2-methyl-1- [3- (4-morpholinyl) propyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 (3H ) -On trifluoroacetate The title compound was synthesized using the techniques described in Example 58, Step C and Example 50, Step E, replacing N-ethylmethylamine with morpholine. ¹ H NMR (TFA salt, 300 MHz, DMSO-d ₆ ) δ 2.2 (m, 2H) 2.7 (s, 3H) 3.1 (m, 2H) 3.3 (m, 2H) 3.4 ( m, 2H) 3.6 (m, 2H) 4.0 (m, 2H) 4.4 (t, J = 5.7 Hz, 2H) 7.6 (m, 3H) 7.9 (m, 4H) 8.0 (s, 1H) 8.5 (s, 1H) 10.1 (bs, 1H). ES-LCMS m / z = 520 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- (1- {3-[(3S) -3-hydroxy-1-pyrrolidinyl] propyl} -2-methyl-1H-benzimidazol-5-yl) thieno [3,2 -D] pyrimidin-4 (3H) -one trifluoroacetate The technique described in Example 58, Step C and Example 50, Step E was used, replacing N-ethylmethylamine with (3S) -3-pyrrolidinol. The title compound was synthesized. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.8 (m, 1H) 1.9 (m, 1H) 2.1 (m, 2H) 2.3 (m, 2H) 2.5 (m, 3H) 2 .7 (m, 4H) 2.9 (m, 1H) 4.3 (t, J = 6.9 Hz, 2H) 4.4 (bs, 1H) 7.3 (s, 1H) 7.3 (dd , J = 8.3, 1.9 Hz, 1H) 7.5 (m, 3H) 7.6 (s, 1H) 7.7 (m, 3H) 8.2 (s, 1H). ES-LCMS m / z = 533 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- {2-methyl-1- [3- (4-methyl-1-piperazinyl) propyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine -4 (3H) -one trifluoroacetate Using the techniques described in Example 58, Step C and Example 50, Step E, replacing N-ethylmethylamine with 1-methylpiperazine, the title compound was prepared. Synthesized. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.3 (m, 2H) 2.8 (m, 3H) 2.9 (bs, 3H) 3.6 (bs, 8H) 4.6 (m, 2H) ) 7.6 (dt, J = 8.6, 1.9 Hz, 2H) 7.7 (d, J = 8.6 Hz, 1H) 7.9 (dt, J = 8.6, 2.1 Hz, 2H) ) 8.0 (s, 1H) 8.1 (d, J = 1.4 Hz, 1H) 8.2 (d, J = 8.4 Hz, 1H) 8.5 (s, 1H). ES-LCMS m / z = 520 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- {2-methyl-1- [2- (1-pyrrolidinyl) ethyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 (3H ) -One trifluoroacetate Example 50, Steps A and B, Example 58, Step A, and Example 50, replacing 3-amino-1-propanol with [2- (1-pyrrolidinyl) ethyl] amine, The title compound was synthesized sequentially using the technique described in Step E. ¹ H NMR (TFA salt, 400 MHz, DMSO-d ₆ ) δ1.9 (m, 2H) 2.0 (m, 2H) 2.7 (s, 3H) 3.2 (m, 2H) 3.6 ( m, 4H) 4.7 (t, J = 4.0 Hz, 2H) 7.5 (dd, J = 8.8, 1.7 Hz, 1H) 7.6 (dt, J = 8.6, 2.. 1 Hz, 2H) 7.9 (m, 4H) 8.0 (s, 1H) 8.4 (s, 1H) 10.2 (bs, 1H). ES-LCMS m / z = 490 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- {2-methyl-1- [2- (4-morpholinyl) ethyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 (3H ) -One trifluoroacetate [2 (1-pyrrolidinyl) ethyl] amine was replaced with [2- (4-morpholinyl) ethyl] amine using the technique described in Example 63 to synthesize the title compound. did. ¹ H NMR (TFA salt, 300 MHz, DMSO-d ₆ ) δ 2.7 (s, 3H) 3.3 (m, 2H) 3.5 (m, 2H) 3.8 (m, 4H) 4.5 ( m, 2H) 4.7 (t, J = 6.9 Hz, 2H) 7.6 (dd, J = 8.6, 1.7 Hz, 1H) 7.6 (dt, J = 8.8, 1. 9 Hz, 2H) 7.9 (m, 2H) 8.0 (dt, J = 8.8, 2.2 Hz, 2H) 8.0 (s, 1H) 8.5 (s, 1H). ES-LCMS m / z = 506 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1-propyl-1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetic acid salt

Step A: N, N-dimethyl-5-nitro-1H-benzimidazol-2-amine 4-nitro-1,2-benzenediamine (25 g, 163 mmol) and chloride (dichloromethylene) in 150 mL of 1,2-dichloroethane Dimethylammonium (“phosgeneiminium chloride”) (26.5 g, 163 mmol) was treated with triethylamine (45 mL, 326 mmol) and stirred overnight. The reaction was rinsed with water and the organic layer was dried over magnesium sulfate, filtered and concentrated to give the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.1 (s, 6H) 7.2 (d, J = 9.0 Hz, 1H) 7.9 (s, 2H) 11.8 (brs, 1H).

Step B:
N, N-dimethyl-6-nitro-1- (2-propen-1-yl) -1H-benzimidazol-2-amine and N, N-dimethyl-5-nitro-1- (2-propen-1- Yl) -1H-benzimidazol-2-amine N, N-dimethyl-5-nitro-1H-benzimidazol-2-amine (1.92 g, 9.3 mmol) in 10 mL of dimethylformamide was added to sodium hydride (560 mg, 14.0 mmol) and stirred for 10 minutes. To this, allyl iodide (1.28 mL, 14 mL) was added and the reaction was stirred for 1 hour. The reaction was diluted with ethyl acetate and rinsed 3 times with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give the desired product mixture. The isomers were analyzed via SFC on a 4.6 × 250 mm Berger Amino Column. The isomers were eluted and separated using a 10:90 methanol: CO2 isocratic mobile phase at 3000 psi, 40 ° C. and a flow rate of 2 mL / min. The elution times of the isomers were N, N-dimethyl-6-nitro-1- (2-propen-1-yl) -1H-benzimidazol-2-amine and N, N-dimethyl-5-nitro-1- About 3.3 and 4.0 min for (2-propen-1-yl) -1H-benzimidazol-2-amine, respectively, where the isomers were assigned by NMR nOne. Isolation of isomers using 8% methanol in CO2, total flow rate 90 g / min, BHK Labs Amino column, 30 × 250 mm 5 u, pressure 145 bar, temperature 40 ° C., UV 250 nm, approximately 50 mg injection every 6 minutes. did. N, N-dimethyl-6-nitro-1- (2-propen-1-yl) -1H-benzimidazol-2-amine N, N-dimethyl-6-nitro-1- (2-propen-1-yl) ) -1H-benzimidazol-2-amine. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.1 (s, 6H) 4.8 (8.1 for s, 2H, nOe) 5.0 (d, J = 17.3 Hz, 1H) 5.3 (D, J = 10.2 Hz, 1H) 6.1 (m, 1H) 7.4 (d, J = 8.6 Hz, 1H) 8.0 (d, J = 9.0 Hz, 1H) 8.1 (S, 1H).

N, N-dimethyl-5-nitro-1- (2-propen-1-yl) -1H-benzimidazol-2-amine. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.0 (s, 6H) 4.8 (7.4 for s, 2H, nOe) 5.0 (d, J = 17.7 Hz, 1H) 5.3 (D, J = 9.6 Hz, 1H) 6.1 (m, 1H) 7.4 (d, J = 8.7 Hz, 1H) 8.0 (d, J = 8.7 Hz, 1H) 8.2 (S, 1H).

Step C: 6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1-propyl-1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one Trifluoroacetate N, N-dimethyl-1- (3-morpholin-4-ylpropyl) -5-nitro-1H-benzimidazol-2-amine was converted to N, N-dimethyl-5-nitro-1- (2 The title compound was synthesized using the technique described in Example 50, Step E, instead of -propen-1-yl) -1H-benzimidazol-2-amine. ¹ H NMR (TFA salt, 400 MHz, DMSO-d ₆ ) δ 0.9 (t, J = 7.2 Hz, 3H) 1.8 (m, 2H) 3.2 (s, 6H) 4.2 (t, J = 7.6 Hz, 2H) 7.4 (d, J = 8.3 Hz, 1H) 7.6 (dt, J = 8.6, 1.9 Hz, 2H) 7.6 (d, J = 1. 9 Hz, 1H) 7.8 (d, J = 8.4 Hz, 1H) 7.9 (dt, J = 8.6, 1.9 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H). APCI-LCMS m / z = 464 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1- (3-hydroxypropyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidine-4 (3H) -On trifluoroacetate

Step A: 3- [2- (Dimethylamino) -5-nitro-1H-benzimidazol-1-yl] -1-propanol N, N-dimethyl-5-nitro-1- (2-propen-1-yl ) -1H-benzimidazol-2-amine (Example 65, intermediate formed in Step B, 100 mg, 0.406 mmol) in THF was cooled to 0 ° C., followed by 9-borabicyclo [3.3. 1] Nonane (0.5 M in THF, 2.4 mL, 1.2 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water (0.66 mL) was then added followed by aqueous sodium hydroxide (10N, 0.27 mL) and hydrogen peroxide (30%, 0.66 mL) was added dropwise. The reaction mixture was stirred three times, concentrated and purified using silica gel (0-10% methanol / dichloromethane) to give the title compound as a yellow solid (62 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ2.1 (m, 2H) 3.6 (m, 6H) 4.3 (t, J = 6.9 Hz, 2H) 7.3 (d, J = 9.5 Hz) , 1H) 8.1 (dd, J = 8.8, 2.2 Hz, 1H) 8.5 (d, J = 2.1 Hz, 1H). APCI-LCMS m / z = 265 (m + H ^< + ^> ).

Step B: 6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1- (3-hydroxypropyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidine-4 (3H) -one trifluoroacetate N, N-dimethyl-1- (3-morpholin-4-ylpropyl) -5-nitro-1H-benzimidazol-2-amine is converted to 3- [2- (dimethylamino) The title compound was synthesized using the technique described in Example 50, Step E, instead of -5-nitro-1H-benzimidazol-1-yl] -1-propanol. ¹ H NMR (TFA salt, 400 MHz, DMSO-d ₆ ) δ 2.0 (m, 2H) 3.2 (s, 6H) 3.5 (t, J = 5.6 Hz, 2H) 4.3 (m, 2H) 7.4 (m, 1H) 7.6 (dt, J = 8.6, 1.7 Hz, 2H) 7.6 (m, 1H) 7.7 (m, 1H) 7.9 (dt, J = 8.6, 2.1 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H). APCI-LCMS m / z = 480 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1-propyl-1H-benzimidazol-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one methanesulfonic acid Salt N, N-dimethyl-1- (3-morpholin-4-ylpropyl) -5-nitro-1H-benzimidazol-2-amine is converted to N, N-dimethyl-6-nitro-1- (2-propene- The title compound was synthesized using the technique described in Example 50, Step E, instead of 1-yl) -1H-benzimidazol-2-amine. ¹ H NMR (MsOH salt, 400 MHz, DMSO-d ₆ ) δ 0.9 (t, J = 7.4 Hz, 3H) 1.8 (m, 2H), 2.3 (s, 3H), 3.3 ( s, 6H) 4.2 (t, J = 7.6 Hz, 2H) 7.5 (dd, J = 8.4, 1.4 Hz, 1H) 7.6 (m, 3H) 7.9 (dt, J = 8.9, 2.7 Hz, 2H) 8.0 (m, 1H) 8.0 (s, 1H) 8.5 (s, 1H). APCI-LCMS m / z = 464 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1- (3-hydroxypropyl) -1H-benzimidazol-6-yl] thieno [3,2-d] pyrimidine-4 (3H) -On trifluoroacetic acid (salt)
N, N-dimethyl-5-nitro-1- (2-propen-1-yl) -1H-benzimidazol-2-amine (intermediate prepared in Example 65, Step A) was converted to N, N-dimethyl. Instead of -6-nitro-1- (2-propen-1-yl) -1H-benzimidazol-2-amine, using the techniques described in Example 66, Step A and Example 50, Step E, The title compound was synthesized. ¹ H NMR (TFA salt, 400 MHz, DMSO-d ₆ ) δ 2.0 (m, 2H) 3.2 (s, 6H) 3.5 (t, J = 5.3 Hz, 2H) 4.3 (t, J = 7.1 Hz, 2H) 7.4 (d, J = 7.8 Hz, 1H) 7.6 (d, J = 8.3 Hz, 1H) 7.6 (dt, J = 8.8, 2. 1 Hz, 2H) 7.9 (m, 1H) 7.9 (dt, J = 8.6, 2.1 Hz, 2H) 8.0 (s, 1H) 8.5 (s, 1H). APCI-LCMS m / z = 480 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- {2-methyl-3- [3- (1-pyrrolidinyl) propyl] -3H-imidazo [4,5-b] pyridin-6-yl} thieno [3,2- d] Pyrimidine-4 (3H) -trifluoroacetic acid (salt)
Example 50, Steps A and B, replacing 2,4-dinitrofluorobenzene with 2-chloro-3,5-dinitropyridine and 3-amino-1-propanol with [3- (1-pyrrolidinyl) propyl] amine The title compound was synthesized using the techniques described in, C, D and E. ¹ H NMR (TFA salt, 400 MHz, DMSO-d ₆ ) δ 1.8 (m, 2H) 2.0 (m, 2H) 2.2 (m, 2H) 2.7 (s, 3H) 3.0 ( m, 2H) 3.2 (m, 2H) 3.6 (m, 2H) 4.4 (t, J = 6.7 Hz, 2H) 7.6 (dt, J = 8.8, 2.1 Hz, 2H) 7.9 (dt, J = 8.6, 2.1 Hz, 2H) 8.0 (s, 1H) 8.2 (d, J = 2.2 Hz, 1H) 8.5 (d, J = 2.1 Hz, 1H) 8.5 (s, 1H) 9.5 (s, 1H). APCI-LCMS m / z = 505 (m + H ^< + ^> ).

6- (4-Fluorophenyl) -3- {2-methyl-1- [3- (4-morpholinyl) propyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 ( 3H) -Trifluoroacetate A solution of methyl 3-amino-5- (4-fluorophenyl) -2-thiophenecarboxylate (160 mg, 0.64 mmol) in N, N-dimethylformamide dimethyl acetal (2 mL) And stirred for 90 minutes and concentrated. The title compound was synthesized using the techniques described in Example 60, replacing methyl 3-amino-5- (4-chlorophenyl) -2-thiophenecarboxylate with this crude material. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.2 (m, 2H) 2.8 (s, 3H) 3.1 (m, 2H) 3.3 (m, 2H) 3.4 (m, 2H) ) 3.6 (m, 2H) 4.0 (m, 2H) 4.5 (t, J = 7.2 Hz, 2H) 7.4 (tt, J = 8.8, 1.9 Hz, 2H) 7 .7 (dd, J = 8.7, 1.8 Hz, 1H) 8.0 (m, 5H) 8.5 (s, 1H). ES-LCMS m / z = 504 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1- (2-hydroxyethyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidine-4 (3H) -ON

Step A:
2- [2- (dimethylamino) -6-nitro-1H-benzimidazol-1-yl] ethanol and 2- [2- (dimethylamino) -5-nitro-1H-benzimidazol-1-yl] ethanol Following a procedure similar to that of Example 65, Step B, substituting 2-bromo-1-ethanol, the desired product mixture was obtained. These were separated using 10% methanol in CO ₂ with a total flow rate of 90 g / min, BHK Labs Amino column 30 × 250 mm 5 u, pressure 140 bar, temperature 30 ° C., UV 230 nm, approximately 65 mg injection every 15 minutes. The initial eluting isomer was 2- [2- (dimethylamino) -6-nitro-1H-benzimidazol-1-yl] ethanol as determined by nOe. 2- [2- (Dimethylamino) -6-nitro-1H-benzimidazol-1-yl] ethanol, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.1 (s, 6H) 3.8 (m, 2H) 4.3 (t, J = 5.4 Hz, 8.3 for 2 H, nOe) 5.1 (m, 1H) 7.4 (d, J = 8.7 Hz, 1H) 8.0 (dd , J = 8.9, 2.4 Hz, 1H) 8.3 (d, J = 2.2 Hz, 1H).

2- [2- (Dimethylamino) -5-nitro-1H-benzimidazol-1-yl] ethanol, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.0 (s, 6H) 3.8 (q, J (5.5 Hz, 2H) 4.2 (t, J = 5.7 Hz, 2 H, nOe 7.6) 5.1 (t, J = 5.5 Hz, 1H) 7.6 (d, J = 8.7 Hz, 1H) 8.0 (dd, J = 8.9, 2.4 Hz, 1H) 8.1 (d, J = 2.0 Hz, 1H).

Step B: 6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1- (2-hydroxyethyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidine-4 (3H) -one N, N-dimethyl-1- (3-morpholin-4-ylpropyl) -5-nitro-1H-benzimidazol-2-amine is converted to 2- [2- (dimethylamino) -5-nitro. The title compound was synthesized using the technique described in Example 50, Step E, instead of [-1H-benzimidazol-1-yl] ethanol. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.3 (s, 6H) 3.8 (m, 2H) 4.4 (m, 2H) 7.5 (m, 1H) 7.6 (m, 3H) ) 7.8 (m, 1H) 7.9 (m, 2H) 8.0 (m, 1H) 8.4 (s, 1H). APCI-LCMS m / z = 466 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1- (2-hydroxyethyl) -1H-benzimidazol-6-yl] thieno [3,2-d] pyrimidine-4 (3H) -On trifluoroacetate salt 2- [2- (dimethylamino) -5-nitro-1H-benzimidazol-1-yl] ethanol was converted to 2- [2- (dimethylamino) -6-nitro-1H-benzimidazole- The title compound was synthesized using the technique described in Example 50, Step E, instead of 1-yl] ethanol. ¹ H NMR (TFA salt, 400 MHz, DMSO-d ₆ ) δ 2.3 (s, 3H) 3.3 (s, 6H) 3.8 (m, 2H) 4.4 (m, 2H) 7.5 ( d, J = 8.6 Hz, 1H) 7.6 (m, 3H) 7.9 (m, 3H) 8.0 (s, 1H) 8.5 (s, 1H). APCI-LCMS m / z = 466 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- {2- (dimethylamino) -1- [2- (methyloxy) ethyl] -1H-benzimidazol-6-yl} thieno [3,2-d] pyrimidine-4 (3H) -one trifluoroacetate

Step A: N, N-dimethyl-1- [2- (methyloxy) ethyl] -6-nitro-1H-benzimidazol-2-amine 2- [2- (dimethylamino) -6-nitro-1H-benz Imidazol-1-yl] ethanol (Example 71, intermediate obtained in Step A, 104 mg) in THF was treated with methyl iodide (80 μL), cooled to 0 ° C. and sodium hydride (35 mg, 60 mg). % Suspension). The reaction was stirred for 1 hour, quenched with methanol and purified by column chromatography to give the title compound as a yellow solid (64 mg). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.1 (s, 6H) 3.4 (s, 3H) 3.8 (t, J = 5.5 Hz, 2H) 4.3 (t, J = 5.5 Hz , 2H) 7.5 (d, J = 8.8 Hz, 1H) 8.1 (dd, J = 8.8, 2.2 Hz, 1H) 8.2 (d, J = 2.2 Hz, 1H). APCI-LCMS m / z = 265 (m + H ^< + ^> ).

Step B: 6- (4-Chlorophenyl) -3- {2- (dimethylamino) -1- [2-"(methyloxy) ethyl] -1H-benzimidazol-6-yl} thieno [3,2-d ] Pyrimidin-4 (3H) -one trifluoroacetate salt 2- [2- (dimethylamino) -5-nitro-1H-benzimidazol-1-yl] ethanol was added to N, N-dimethyl-1- [2- ( The title compound was synthesized using the technique described in Example 50, Step E, instead of methyloxy) ethyl] -6-nitro-1H-benzimidazol-2-amine ¹ H NMR (TFA salt, 300 MHz, DMSO-d ₆ ) δ 3.2 (s, 6H) 3.8 (t, J = 5.2 Hz, 2H) 4.4 (t, J = 5.2 Hz, 2H) 7.5 (dd, J = 8.7, 1.5 Hz, 1H 7.6 (m, 3H) 7.9 (m, 1H) 8.0 (dt, J = 8.8, 2.2 Hz, 2H) 8.0 (s, 1H) 8.5 (s, 1H) APCI-LCMS m / z = 480 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- {1- [2- (4-morpholinylethyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidin-4 (3H) -one Trifluoroacetate

Step A: 1- [2- (4-morpholinyl) ethyl] -5-nitro-1H-benzimidazole N ^1- [2- (4-morpholinyl) ethyl] -4-nitro-1,2-benzenediamine (implementation) A DMF solution of the compound synthesized in Example 93, Step B) was treated with concentrated aqueous hydrochloric acid, heated to 100 ° C. and stirred for 4 hours. The reaction mixture was cooled and purified using silica gel to give the title compound. ES-LCMS m / z = 277 (m + H ^< + ^> ).

Step B: 6- (4-Chlorophenyl) -3- {1- [2- (4-morpholinyl) ethyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 (3H) -On trifluoroacetate salt 2- [2- (dimethylamino) -5-nitro-1H-benzimidazol-1-yl] ethanol with 1- [2- (4-morpholinyl) ethyl] -5-nitro-1H- The title compound was synthesized using the technique described in Example 50, Step E, instead of benzimidazole. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.2 (m, 2H) 3.6 (m, 6H) 4.0 (m, 2H) 4.7 (m, 2H) 7.5 (dd, J = 8.5, 2.0 Hz, 1H) 7.6 (dt, J = 8.8, 2.1 Hz, 2H) 7.9 (m, 4H) 8.0 (s, 1H) 8.4 (s , 1H) 8.5 (m, 1H). ES-LCMS m / z = 492 (m + H ^< + ^> ).

6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetate

Step A: 2-Chloro-5-nitro-1H-benzimidazole Concentrated HNO ₃ (8 mL) is a mixture of 2-chloro-1H-benzimidazole (4 g, 26.22 mmol) and concentrated H ₂ SO ₄ (25 mL). At 0 ° C. The mixture was stirred at 0 ° C. for 1 hour. The reaction was charged with ice water (200 mL) and then extracted with EtOAc. The organics were dried over MgSO ₄ (anhydrous), filtered and concentrated to dryness. The resulting crude was purified by silica gel chromatography (0-50% EtOAc / hexanes with a 30 minute gradient, then 50% EtOAc / hexanes for 30 minutes). The resulting material was repurified by silica gel chromatography (35% EtOAc / hexanes) to give the title compound as a white solid (2.64 g, 51% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.7 (d, J = 8.8 Hz, 1H) 8.1 (dd, J = 8.9, 2.3 Hz, 1H) 8.4 (d, J = 2.1 Hz, 1 H). ES-LCMS m / z 197 (100), (M + H).

Step B: 2-Chloro-1H-benzimidazol-5-amine 2-Chloro-5-nitro-1H-benzimidazole (Example 75, Step A, 2.15 g, 10.88 mmol) was added to Sn (II) Cl. _{To a} solution of 2.2H ₂ O (8.59 g, 38.08 mmol) in concentrated HCl (30 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 15 minutes and then at 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature, poured onto ice (100 g) and then brought to pH 8 with 10 N NaOH (aq). The mixture was charged with Rochelle salt and then extracted with EtOAc. The organics were dried over MgSO ₄ (anhydrous), filtered and concentrated to dryness to give the title compound as a white solid (1.53 g, 84% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ4.9 (s, 2H) 6.5 (dd, J = 8.4, 1.7 Hz, 1H) 6.5 (s, 1H) 12.5 (s , 1H). ES-LCMS m / z 168 (100), (M + H).

Step C: 6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetate A mixture consisting of 2-chloro-1H-benzimidazol-5-amine (Example 75, Step B, 50 mg, 0.3 mmol), dimethylamine (0.5 mL) and EtOH (3 mL) in a pressure tube at 100 ° C. Stir for 25 hours. Additional dimethylamine (3 mL) was added and the mixture was stirred in a pressure tube at 160 ° C. for 23 hours. The reaction was cooled and concentrated to dryness, intermediate ^N 2, ^{N 2} - dimethyl -1H- benzimidazole-2,5-diamine ES-LCMS m / z 177 ( M + H) was obtained. A mixture of methyl 3-amino-5- (4-chlorophenyl) -2-thiophenecarboxylate (80 mg, 0.3 mmol) and N, N-dimethylformamide dimethyl acetal (3 mL) was stirred at 110 ° C. for 30 minutes. Next, the reaction solution was concentrated to dryness, and the resulting crude product was charged with an EtOA (5 mL) solution of the intermediate (N ² , N ² -dimethyl-1H-benzimidazole-2,5-diamine). The mixture was stirred at reflux for 19 hours. The reaction was concentrated to dryness, taken up in DMSO and purified by C18 preparative HPLC (1-99% CH ₃ CN / H ₂ O with 5 min gradient) to give the title compound off-white (39 mg Yield 24%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.2 (m, 6H) 7.4 (dd, J = 8.3, 1.7 Hz, 1H) 7.5 (d, J = 8.4 Hz, 1H) 7.6 (d, J = 8.2 Hz, 2H) 7.6 (d, J = 1.8 Hz, 1H) 7.9 (d, J = 8.2 Hz, 2H) 8.0 (d, J = 0.7 Hz, 1 H) 8.4 (d, J = 0.7 Hz, 1 H). APCI-LCMS m / z 422 (100), (M + H).

3- (2-Amino-1-phenyl-1H-benzimidazol-5-yl) -6- (4-chlorophenyl) thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetate

Step A: 4-Nitro-N ¹ -phenyl-1,2-benzenediamine Na ₂ S ₂ O ₄ (20.15 g, 115.73 mmol) in H ₂ O (50 mL) was added to EtOH (50 mL) and 2- To a solution of 2,4-dinitro-N-phenylaniline (10 g, 38.58 mmol) in propanol (100 mL). The mixture was stirred at reflux for 1 hour. The mixture was concentrated, charged with H ₂ O and extracted with CH ₂ Cl ₂ . The resulting crude mixture is purified by silica gel chromatography (25% EtOAc / hexanes) to give the title compound as a red solid (3.8 g, 43% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.4 (s, 2H) 7.0 (dd, J = 7.3 Hz, 1H) 7.0 (d, J = 8.8 Hz, 1H) 7.1 (Dd, J = 8.6, 1.0 Hz, 2H) 7.3 (t, 2H) 7.4 (dd, J = 8.9, 2.7 Hz, 1H) 7.6 (d, J = 2 .8 Hz, 1H) 7.8 (s, 1H). APCI-LCMS m / z 228 (100), (M-H).

Step B: 5-Nitro-1-phenyl-1H-benzimidazol-2-amine 3M cyanogen bromide (6.6 mL, 16.95 mmol) in CH ₂ Cl _{2 was} added to 4-nitro-N ¹ -phenyl-1 , 2-benzenediamine (Example 76, Step A, 2.59 g, 11.3 mmol) and CH ₂ Cl ₂ (100 mL) were added. The reaction was stirred at room temperature for 24 hours. The mixture was concentrated to dryness and the resulting crude was purified by silica gel chromatography (0-5% MeOH / CH ₂ Cl _{2 with} a 25 minute gradient, then 10%, 5% MeOH / CH ₂ Cl ₂ ). The title compound was then obtained as an orange solid (2.85 g, 99% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.1 (d, J = 8.8 Hz, 1H) 7.7 (m, 5H) 8.1 (dd, J = 8.8, 2.2 Hz, 1H ) 8.2 (d, J = 2.2 Hz, 1H) 8.9 (s, 2H). APCI-LCMS m / z 255 (100), (M + H).

Step C: 1-Phenyl-1H-benzimidazole-2,5-diamine Na ₂ S ₂ O ₄ (616 mg, 3.54 mmol) in H ₂ O (2 mL) was added to 5-nitro-1-phenyl-1H— Benzimidazol-2-amine (Example 76, Step B, 300 mg, 1.18 mmol) was added to a solution of EtOH (25 mL) at reflux. The mixture was stirred and refluxed for 1 hour. The mixture was concentrated and the resulting crude was purified by silica gel chromatography (10% MeOH / CH ₂ Cl ₂ ) to give the title compound as a clear oil (80 mg, 30% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.2 (dd, J = 8.2, 2.0 Hz, 1H) 6.5 (m, J = 2.0 Hz, 1H) 6.6 (d, J = 8.4 Hz, 1H) 7.5 (m, 3H) 7.6 (t, J = 7.8 Hz, 2H). APCI-LCMS m / z 225 (70), (M + H).

Step D: 3- (2-Amino-1-phenyl-1H-benzimidazol-5-yl) -6- (4-chlorophenyl) thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetic acid Salt A mixture of methyl 3-amino-5- (4-chloro-phenyl) -2-thiophenecarboxylate (96 mg, 0.36 mmol) and N, N-dimethylformamide dimethyl acetal (3 mL) was stirred at 110 ° C. for 30 minutes. did. The reaction was then concentrated to dryness and the resulting crude product was combined with 1-phenyl-1H-benzimidazole-2,5-diamine (Example 76, Step C, 80 mg, 0.36 mmol) and EtOH (5 mL). Filled. The mixture was stirred and refluxed for 17 hours. The reaction was concentrated to dryness, taken up in DMSO and purified by C18 preparative HPLC (1-99% CH ₃ CN / H ₂ O, 5 min gradient) to give the title compound as an off-white solid. (35 mg, 17% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.1 (d, J = 8.4 Hz, 1H) 7.3 (dd, J = 8.7, 1.8 Hz, 1H) 7.6 (d, J = 8.4 Hz, 2H) 7.7 (m, 6H) 7.9 (d, J = 8.6 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H). APCI-LCMS m / z 470 (100), (M + H)

6- (4-Chlorophenyl) -3- [2- (4-morpholinyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetate

Step A: 2- (4-morpholinyl) -1H-benzimidazol-5-amine 2-chloro-1H-benzimidazol-5-amine (Example 75, Step B, 60 mg, 0.36 mmol), morpholine (0. 5 mL) and EtOH (5 mL) were stirred at reflux for 64 hours. The mixture was then stirred in a pressure tube at 130 ° C. for 2 hours. The reaction was concentrated to dryness to give the title compound as an orange solid (130 mg, quantitative yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.5 (m, 1H) 3.0 (m, 2H) 3.3 (m, 2H) 3.7 (m, 3H) 6.3 (dd, J = 8.3, 2.1 Hz, 1H) 6.5 (d, J = 1.7 Hz, 1H) 6.9 (d, J = 8.3 Hz, 1H). APCI-LCMS m / z 217 (100), (M-H).

Step B: 6- (4-Chlorophenyl) -3- [2- (4-morpholinyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetic acid Salt Using the same experimental procedure as in Example 76, Step D, except that 1-phenyl-1H-benzimidazole-2,5-diamine is 2- (4-morpholinyl) -1H-benzimidazole-5. Substitution for the amine (Example 77, Step A, 74 mg, 0.34 mmol) gave the title compound as an off-white solid (45 mg, 23% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.6 (m, 4H) 3.8 (m, 4H) 7.4 (dd, J = 8.5, 1.7 Hz, 1H) 7.5 (D, J = 8.4 Hz, 1H) 7.6 (d, J = 8.6 Hz, 2H) 7.6 (s, 1H) 7.9 (d, J = 8.8 Hz, 2H) 8.0 (S, 1H) 8.4 (s, 1H). ES-LCMS m / z 464 (100), (M + H).

6- (4-Chlorophenyl) -3- [2- (4-methyl-1-piperazinyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoro Acetate

Step A: 2- (4-Methyl-1-piperazinyl) -1H-benzimidazol-5-amine 2-chloro-1H-benzimidazol-5-amine (Example 75, Step B, 100 mg, 0.6 mmol) and A mixture consisting of 1-methylpiperazine (2 mL) was stirred in a pressure tube at 130 ° C. for 2.5 hours. The reaction was concentrated to dryness and the resulting crude was purified by silica gel chromatography (15% MeOH / CH ₂ Cl ₂ ) to give the title compound as a brown oil (113 mg, 84% yield). . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.2 (s, 3H) 2.4 (m, 3H) 3.0 (m, 3H) 3.4 (m, 2H) 6.2 (dd, J = 8.3, 2.1 Hz, 1H) 6.4 (d, J = 2.1 Hz, 1H) 6.8 (d, J = 8.1 Hz, 1H). APCI-LCMS m / z 232 (80), (M + H).

Step B: 6- (4-Chlorophenyl) -3- [2- (4-methyl-1-piperazinyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidine-4 (3H)- Ontrifluoroacetate salt Using the same experimental procedure as Example 76, Step D, 1-phenyl-1H-benzimidazole-2,5-diamine was converted to 2- (4-methyl-1-piperazinyl) -1H— The title compound was prepared in place of benzimidazol-5-amine (Example 78, Step A, 113 mg, 0.49 mmol) to give the title compound as an off-white solid (24 mg, 8% yield). It was. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.8 (s, 3H) 3.2 (m, 4H) 3.4 (m, 4H) 7.2 (d, J = 10.3 Hz, 1H) 7 .5 (d, J = 8.3 Hz, 1H) 7.5 (s, 1H) 7.6 (d, J = 8.8 Hz, 2H) 7.9 (d, J = 8.6 Hz, 2H) 8 0.0 (s, 1H) 8.4 (s, 1H). APCI-LCMS m / z 477 (100), (M + H).

6- (4-Chlorophenyl) -3- [2- (1-piperidinyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetate

Step A: 2- (1-Piperidinyl) -1H-benzimidazol-5-amine 2-Chloro-1H-benzimidazol-5-amine (Example 75, Step B, 100 mg, 0.6 mmol), piperidine (2 mL) And a mixture of EtOH (2 mL) was stirred in a pressure tube at 160 ° C. for 17 hours. The reaction was concentrated to dryness and the resulting crude was purified by silica gel chromatography (0-10% MeOH / CH ₂ Cl ₂ , 20 min gradient, then 10% MeOH / CH ₂ Cl ₂ , 20 min). Purification gave the title compound as a brown solid (111 mg, 86% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.6 (m, 4H) 1.6 (m, 2H) 3.0 (m, 2H) 3.3 (s, 2H) 6.3 (dd, J = 8.1, 2.1 Hz, 1H) 6.5 (d, J = 2.1 Hz, 1H) 6.9 (d, J = 8.3 Hz, 1H). APCI-LCMS m / z 217 (100), (M + H).

Step B: 6- (4-Chlorophenyl) -3- [2- (1-piperidinyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetic acid Salt 2- (1-piperidinyl) -1H-benzimidazol-5-amine (Example 79, Step A, 111 mg, 0.51 mmol), 5- (4-chlorophenyl) -3-{[(1E)-(dimethyl A mixture of methyl amino) methylidene] amino} -2-thiophenecarboxylate (Example 1, Step D, 166 mg, 0.51 mmol) and EtOH (5 mL) was stirred and refluxed for 24 hours. The reaction was concentrated to dryness, taken up in DMSO and purified by C18 preparative HPLC (1-99% CH ₃ CN / H ₂ O, 5 min gradient) to give the title compound as a white solid (45 mg, Yield 15%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.7 (m, 6H) 3.6 (s, 4H) 7.4 (dd, J = 8.4, 1.9 Hz, 1H) 7.5 (D, J = 8.4 Hz, 1H) 7.6 (d, 2H) 7.6 (d, J = 1.9 Hz, 1H) 7.9 (d, 2H) 8.0 (s, 1H) 8 .4 (s, 1H). ES-LCMS m / z 462 (100), (M + H).

3- (2-Amino-1H-benzimidazol-5-yl) -6- (4-chlorophenyl) thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetate

Step A: 5-Nitro-1H-benzimidazol-2-amine (2-amino-4-nitrophenyl) amine (3 g, 19.6 mmol), 3M cyanogen bromide in CH ₂ Cl ₂ (6.53 mL, 19 .6 mmol), MeOH (50 mL) and H ₂ O (50 mL) were stirred at room temperature for 18 hours. Concentrate the reaction to dryness and purify the resulting crude by silica gel chromatography (0-10% MeOH / CH ₂ Cl ₂ , 30 min gradient, then 10% MeOH / CH ₂ Cl ₂ , 30 min). Then, the title compound was obtained as an orange solid (2.67 g, yield 77%). ^{1 H NMR (400MHz, DMSO-} d 6) δ7.5 (d, J = 8.6Hz, 1H) 8.1 (dd, 1H) 8.1 (d, 1H) 8.9 (s, 2H). ES-LCMS m / z 179 (100), (M + H).

Step B: 1H-benzimidazole-2,5-diamine 5-nitro-1H-benzimidazol-2-amine (Example 80, Step A, 200 mg, 1.12 mmol), 10% Pd / C (20 mg) and EtOH The mixture consisting of (20 mL) was stirred for 17.5 hours under H ₂ atmosphere (1 atm). The reaction was filtered through celite and the filtrate was concentrated to dryness to give the title compound as a purple oil (200 mg, quantitative yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.3 (m, 2H) 6.4 (dd, J = 8.4, 2.1 Hz, 1H) 6.5 (d, J = 1.7 Hz, 1H) ) 7.0 (d, J = 8.4 Hz, 1H) 8.0 (s, 2H). ES-LCMS m / z 149 (100), (M + H).

Step C: 3- (2-Amino-1H-benzimidazol-5-yl) -6- (4-chlorophenyl) thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetate 2- ( 1-piperidinyl) -1H-benzimidazol-5-amine is replaced with 1H-benzimidazole-2,5-diamine (Example 80, Step B, 166 mg, 1.12 mmol), as described in Example 79, Step B The title compound was synthesized using techniques to give the title compound as a yellow solid (155 mg, 27% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.4 (dd, J = 8.4, 2.0 Hz, 1H) 7.5 (d, J = 8.5 Hz, 1H) 7.6 (m, 3H ) 7.9 (d, 2H) 8.0 (s, 1H) 8.4 (s, 1H) 8.7 (s, 2H). APCI-LCMS m / z 394 (100), (M + H).

6- (4-Chlorophenyl) -3- [2- (methylamino) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetate

Step A: N-methyl-5-nitro-1H-benzimidazol-2-amine 2-chloro-5-nitro-1H-benzimidazole (Example 75, Step A, 100 mg, 0.51 mmol) and 2M in MeOH. A mixture consisting of methylamine (5 mL) was stirred in a pressure tube at 160 ° C. for 24 hours. The reaction was cooled and concentrated to dryness to give the title compound as an orange solid (162 mg, quantitative yield). The crude product was used as such in the next step. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.9 (d, J = 3.3 Hz, 3H) 7.2 (m, J = 8.4 Hz, 1H) 7.3 (s, 1H) 7.9 (D, J = 8.4 Hz, 1H) 7.9 (m, J = 2.1 Hz, 1H). ES-LCMS m / z 193 (100), (M + H).

Step B: ^{N 2} - methyl -1H- benzimidazole-2,5-diamine N- methyl-5-nitro -1H- benzimidazol-2-amine (Example 81, Step A, 162 mg, 0.54 mmol), 10 A mixture consisting of% Pd / C (16 mg) and EtOH (25 mL) was stirred under H ₂ atmosphere (1 atm) for 4 hours. The reaction was filtered through celite and the filtrate was concentrated to dryness to give the title compound as a brown oil (131 mg, 96% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ2.9 (s, 3H) 6.3 (dd, J = 8.3, 1.9 Hz, 1H) 6.5 (d, J = 1.9 Hz, 1H) 6.9 (d, J = 8.3 Hz, 1H). ES-LCMS m / z 163 (100), (M + H).

Step C: 6- (4-Chlorophenyl) -3- [2- (methylamino) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetate 2- (1-piperidinyl) -1H-benzimidazol-5-amine) was replaced with N ² -methyl-1H-benzimidazole-2,5-diamine (Example 81, Step B, 131 mg, 0.81 mmol), The title compound was synthesized using the technique described in Example 79, Step B, to give the title compound as a tan solid (40 mg, 9% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.0 (d, J = 4.8 Hz, 3H) 7.4 (dd, J = 8.4, 1.8 Hz, 1H) 7.5 (d, J = 8.4 Hz, 1H) 7.6 (m, J = 8.4 Hz, 3H) 7.9 (d, J = 8.4 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H) 8.9 (s, 1H). ES-LCMS m / z 408 (100), (M + H).

6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1-methyl-1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetic acid salt

Step A: 2-Chloro-1-methyl-1H-benzimidazole Dimethyl sulfate (5.5 mL) consists of 2-chlorobenzimidazole (5 g, 32.77 mmol) and 10 N NaOH (aq) (7.5 mL). To a solution in H ₂ O (57.5 mL) was added dropwise at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 17 hours. The resulting precipitate was filtered, washed with H ₂ O, azeotroped with toluene and placed under high vacuum to dry. The title compound was obtained as an off-white solid (4.04 g, 74% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.8 (s, 3H) 7.3 (m, 2H) 7.6 (m, 2H). APCI-LCMS m / z 167 (50), (M + H).

Step B: 2-Chloro-1-methyl-5-nitro-1H-benzimidazole and 2-chloro-1-methyl-6-nitro-1H-benzimidazole concentrated HNO ₃ (8 mL) were added to 2-chloro-1- To a mixture consisting of methyl-1H-benzimidazole (4.04 g, 24.25 mmol) and concentrated H ₂ SO ₄ (25 mL) was added dropwise at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour. The reaction was charged with ice water (200 mL) and then extracted with EtOAc. The organic layer was dried over MgSO ₄ (anhydrous), filtered and concentrated in vacuo. The resulting crude was purified by silica gel chromatography (0-50% EtOAc / hexane, 30 min gradient, then 50% EtOAc / hexane, 30 min) to give 2-chloro-1-methyl-5-nitro-1H. -Benzimidazole as a yellow solid (552 mg, 11% yield, Rf = 0.625, 50% EtOAc / hexane): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.9 (s, 3H) 8 (d, J = 9.0 Hz, 1H) 8.1 (d, J = 8.9, 2.3 Hz, 1H) 8.7 (m, J = 2.1 Hz, 1H), ES-LCMS m / z 211 (10), (M + H), and 2-chloro-1-methyl-6-nitro-1H-benzimidazole is a yellow solid (142 mg, 3% yield, Rf = 0.5, 50% EtOAc) Was obtained as a hexane). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.9 (s, 3H) 7.8 (d, J = 9.1 Hz, 1H) 8.2 (dd, J = 9.0, 2.2 Hz, 1H ) 8.5 (d, J = 2.1 Hz, 1H), ES-LCMS m / z 211 (100), (M + H).

Step C: N, N, 1-Trimethyl-5-nitro-1H-benzimidazol-2-amine 2-chloro-1-methyl-5-nitro-1H-benzimidazole (Example 82, Step B, 140 mg, 0 .66 mmol), a mixture of 2M dimethylamine in THF (1 mL) and EtOH (15 mL) was stirred at 100 ° C. in a pressure tube for 4 h. The reaction was concentrated to dryness and the resulting crude was purified by silica gel chromatography (10% MeOH / CH ₂ Cl ₂ ) to give the title compound as an orange solid (102 mg, 70% yield). It was. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.3 (s, 3H) 3.7 (s, 6H) 7.5 (s, 1H) 8.0 (d, J = 2.2 Hz, 1H) 8 .2 (d, J = 2.2 Hz, 1H). ES-LCMS m / z 221 (100), (M + H).

Step ^{D: N 2, N 2,} 1- trimethyl -1H- benzimidazole-2,5-diamine N, N, 1-trimethyl-5-nitro--1H- benzimidazol-2-amine (Example 82, Step C , 102 mg, 0.46 mmol), a mixture of 10% Pd / C (10 mg) and MeOH (10 mL) was stirred under H ₂ atmosphere (1 atm) for 1 hour. The reaction was filtered through celite and the filtrate was concentrated to dryness to give the title compound as an orange oil (82 mg, 94% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.8 (s, 6H) 3.5 (s, 3H) 4.5 (s, 7H) 6.4 (dd, J = 8.3, 2.1 Hz , 1H) 6.6 (d, J = 1.9 Hz, 1H) 6.9 (d, J = 8.3 Hz, 1H). ES-LCMS m / z 191 (100), (M + H).

Step E: 6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1-methyl-1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one Trifluoroacetic acid salt 2- (1-piperidinyl) -1H-benzimidazol-5-amine was converted to N ² , N ² , 1-trimethyl-1H-benzimidazole-2,5-diamine (Example 82, Step D, 82 mg). The title compound was synthesized using the technique described in Example 79, Step B, instead of 0.43 mmol, to give the title compound as an off-white solid (16 mg, 7% yield). ^{was. 1 H NMR (400MHz, DMSO} -d 6) δ3.2 (s, 6H) 3.8 (s, 3H) 7.4 (d, J = 8.8Hz, 1H) 7.6 (d, J 8.8 Hz, 2H) 7.6 (d, J = 2.2 Hz, 1H) 7.7 (d, J = 8.4 Hz, 1H) 7.9 (d, J = 8.8 Hz, 2H) 0 (s, 1 H) 8.4 (s, 1 H) ES-LCMS m / z 436 (100), (M + H).

6- (4-Chlorophenyl) -3- {2-[(1-methylethyl) amino] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidin-4 (3H) -one trifluoro Acetate

Step A: N- (1-Methylethyl) -5-nitro-1H-benzimidazol-2-amine 2-chloro-5-nitro-1H-benzimidazole (Example 75, Step A, 150 mg, 0.76 mmol) , Isopropylamine (647 μL, 7.6 mmol) and EtOH (5 mL) were stirred in a pressure tube at 160 ° C. for 23 hours. The reaction is concentrated to dryness and the resulting crude is purified by silica gel chromatography (50-100% EtOAc / hexanes, 30 min gradient, then 100% EtOAc / hexanes, 15 min) to yield the title compound. Obtained as a yellow solid (96 mg, 57% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.2 (s, 3H) 1.2 (s, 3H) 3.3 (s, 1H) 3.9 (m, J = 13.6, 7.0 Hz) , 1H) 7.2 (d, J = 8.8 Hz, 1H) 7.9 (d, J = 8.2 Hz, 1H) 7.9 (d, J = 2.4 Hz, 1H) 11.1 (d , 1H). ES-LCMS m / z 221 (100), (M + H).

Step ^B: N 2 - (1- methylethyl)-1H-benzimidazole-2,5-diamine N-(1-methylethyl) -5-nitro-1H-benzimidazol-2-amine (Example 83, step A mixture of A, 96 mg, 0.43 mmol), 10% Pd / C (10 mg) and MeOH (15 mL) was stirred under H ₂ atmosphere (1 atm) for 2 hours. The reaction was filtered through celite and the filtrate was concentrated to dryness to give the title compound as a brown solid (80 mg, 98% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.1 (s, 3H) 1.1 (s, 3H) 3.8 (m, 1H) 4.3 (s, 1H) 4.4 (s, 2H ) 6.0 (m, 2H) 6.8 (dd, J = 20.3, 8.2 Hz, 1H) 10.1 (d, J = 32.2 Hz, 1H). ES-LCMS m / z 191 (100), (M + H).

Step C: 6- (4-Chlorophenyl) -3- {2-[(1-methylethyl) amino] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 (3H)- Ontrifluoroacetate salt 2- (1-piperidinyl) -1H-benzimidazol-5-amine was converted to N ^2- (1-methylethyl) -1H-benzimidazole-2,5-diamine (Example 83, Step B, The title compound was synthesized using the technique described in Example 79, Step B instead of 80 mg, 0.42 mmol) to give the title compound as an off-white solid (16 mg, 7% yield). As obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.3 (s, 3H) 1.3 (s, 3H) 3.9 (m, 1H) 7.4 (dd, J = 8.4, 1.9 Hz) , 1H) 7.5 (d, J = 8.4 Hz, 1H) 7.6 (m, 3H) 7.9 (m, 2H) 8.0 (s, 1H) 8.4 (s, 1H) 9 .1 (s, 1H). ES-LCMS m / z 436 (100), (M + H).

6- (4-Chlorophenyl) -3- [2- (methylamino) -1-phenyl-1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetic acid salt

Step A: N-methyl-5-nitro-1-phenyl-1H-benzimidazol-2-amine and N, N-dimethyl-5-nitro-1-phenyl-1H-benzimidazol-2-amine NaH (71 mg, 2.96 mmol) was added to a solution of 5-nitro-1-phenyl-1H-benzimidazol-2-amine (Example 76, Step B, 500 mg, 1.97 mmol) in DMF (15 mmL) at 0 ° C. The mixture was stirred at 0 ° C. for 30 minutes and then iodomethane (184 μL, 2.96 mmol) was added at 0 ° C. The mixture was stirred at room temperature for 16 hours. H ₂ O was added to the reaction and extracted with EtOAc. The organics were dried over MgSO ₄ (anhydrous), filtered and concentrated to dryness. The resulting crude was purified by silica gel chromatography (0-80% EtOAc / hexanes, 90 min gradient) to give N-methyl-5-nitro-1-phenyl-1H-benzimidazol-2-amine as a yellow solid (107 mg, 20% yield): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.9 (d, J = 4.6 Hz, 3H) 6.7 (m, J = 4.5, 4.5 , 4.5 Hz, 1H) 6.9 (d, J = 8.8 Hz, 1H) 7.5 (m, 2H) 7.6 (m, 1H) 7.6 (m, 2H) 7.8 (dd , J = 8.7, 2.3 Hz, 1H) 8.1 (d, J = 2.2 Hz, 1H), APCI-LCMS m / z 269 (100), (M + H), and N, N-dimethyl- 5-Nitro-1-phenyl-1H-benzimidazol-2-a Emissions as a yellow solid (79 mg, 14% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ2.8 (s, 6H) 7.0 (d, J = 8.8 Hz, 1H) 7.6 (m, 3H) 7.6 (m, 2H) 7 .9 (dd, J = 8.8, 2.2 Hz, 1H) 8.1 (d, J = 2.2 Hz, 1H), APCI-LCMS m / z 283 (100), (M + H).

Step B: N ² -Methyl-1-phenyl-1H-benzimidazole-2,5-diamine N-methyl-5-nitro-1-phenyl-1H-benzimidazol-2-amine (Example 84, Step A, A mixture consisting of 107 mg, 0.40 mmol), 10% Pd / C (10 mg) and EtOH (20 mL) was stirred under H ₂ atmosphere (1 atm) for 2 hours. The reaction was filtered through celite and the filtrate was concentrated to dryness to give the title compound as a tan residue (94 mg, 99% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.8 (d, J = 4.7 Hz, 3H) 4.5 (s, 2H) 6.0 (d, J = 4.3 Hz, 1H) 6.2 (Dd, J = 8.2, 2.2 Hz, 1H) 6.5 (m, 2H) 7.4 (m, 3H) 7.6 (m, 2H). ES-LCMS m / z 239 (100), (M + H).

Step C: 6- (4-Chlorophenyl) -3- [2- (methylamino) -1-phenyl-1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one Trifluoroacetate N ² -methyl-1-phenyl-1H-benzimidazole-2,5-diamine (Example 84, Step B, 90 mg, 0.38 mmol), 5- (4-chlorophenyl) -3-{[ A mixture of (1E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate (Example 75, Step D, 122 mg, 0.38 mmol) and phenol (2 mL) was stirred and refluxed for 15 minutes. The reaction was further charged with methyl 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate (Example 75, Step D, 61 mg, 0.19 mmol). And stirred at reflux for 15 minutes. The reaction was taken up in DMSO and purified by C18 preparative HPLC (1-99% CH ₃ Cn / H ₂ O, 5 min gradient) to give the title compound as a white solid (55 mg, 24% yield). It was. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.0 (d, J = 4.8 Hz, 3H) 7.1 (d, J = 8.4 Hz, 1H) 7.3 (d, J = 9.0 Hz) , 1H) 7.6 (d, J = 8.8 Hz, 2H) 7.7 (m, 6H) 7.9 (d, J = 8.8 Hz, 2H) 8.0 (s, 1H) 8.4 (S, 1H). ES-LCMS m / z 484 (100), (M + H).

6- (4-Chlorophenyl) -3- [2- (dimethylamino) -1-phenyl-1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetic acid Salt N-methyl-5-nitro-1-phenyl-1H-benzimidazol-2-amine was converted to N-methyl-5-nitro-1-phenyl-1H-benzimidazol-2-amine (Example 84, Step A, The title compound was synthesized by using the technique described in Example 84, Steps B and C instead of 79 mg, 0.28 mmol) to give an off-white solid (21 mg, 13% yield). It was. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ2.9 (s, 6H) 7.0 (d, J = 8.6 Hz, 1H) 7.3 (m, 1H) 7.6 (d, J = 8 .8 Hz, 2H) 7.7 (m, 6H) 7.9 (d, J = 8.6 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H). ES-LCMS m / z 498 (100), (M +).

6- (4-Chlorophenyl) -3- [2- (1-pyrrolidinyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetate

Step A: 5-Nitro-2- (1-pyrrolidinyl) -1H-benzimidazole 2-Chloro-5-nitro-1H-benzimidazole (Example 75, Step A, 100 mg, 0.6 mmol), Pyrrolidine (2 mL) And a mixture of EtOH (10 mL) was stirred in a pressure tube at 160 ° C. for 18 hours. The reaction was concentrated to dryness to give the title compound as a brown oil (213 mg, quantitative yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.0 (m, 4H) 3.5 (m, 4H) 7.2 (dd, J = 8.6, 0.5 Hz, 1H) 7.9 (m , 2H). APCI-LCMS m / z 233 (100), (M + H).

Step B: 2- (1-Pyrrolidinyl) -1H-benzimidazol-5-amine 5-nitro-2- (1-pyrrolidinyl) -1H-benzimidazole (Example 86, Step A: 139 mg, 0.6 mmol), A mixture consisting of 10% Pd / C (10 mg) and MeOH (10 mL) was stirred for 1 h under H ₂ atmosphere (1 atm). The reaction was filtered through celite and the filtrate was concentrated to dryness to give the title compound as a tan solid (186 mg, quantitative yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ1.9 (m, 4H) 3.4 (m, 4H) 6.2 (dd, J = 8.2, 2.2 Hz, 1H) 6.4 (d , J = 2.1 Hz, 1H) 6.8 (d, J = 8.3 Hz, 1H). APCI-LCMS m / z 203 (100), (M + H).

Step C: 6- (4-Chlorophenyl) -3- [2- (1-pyrrolidinyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetic acid Salt 2- (1-pyrrolidinyl) -1H-benzimidazol-5-amine (Example 86, Step B, 121 mg, 0.6 mmol), 5- (4-Chlorophenyl) -3-{[(1E)-(dimethyl A mixture of amino) methylidene] amino} thiophene-2-carboxylate (Example 1, Step D, 86 mg, 0.27 mmol) and phenol (2 mL) was stirred at 200 ° C. for 30 minutes. The mixture was cooled to room temperature and then partitioned between EtOAc and 1N NaOH (aq). The organics were concentrated to dryness and the resulting crude was taken up in DMSO and purified by C18 preparative HPLC (1-99% CH ₃ CN / H ₂ O, 5 min gradient) to give the title compound off-white. As a solid (50 mg, 15% yield). 1 H NMR (400 MHz, DMSO-d ₆ ) δ2.1 (m, 4H) 3.6 (m, 4H) 7.4 (dd, J = 8.3, 1.9 Hz, 1H) 7.5 (d, J = 8.3 Hz, 1H) 7.6 (d, J = 8.6 Hz, 2H) 7.6 (d, J = 1.9 Hz, 1H) 7.9 (d, J = 8.8 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H) 13.0 (s, 1H). ES-LCMS m / z 448 (100), (M + H).

6- (4-Chlorophenyl) -3- [2- (cyclopropylamino) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetate pyrrolidine The title compound was synthesized using the techniques described in Example 86, Steps A, B, and C instead of cyclopropylamine (1 mL) to give an off-white solid (16 mg, 11% yield). It was. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.7 (m, 2H) 0.9 (m, 2H) 2.8 (s, 1H) 7.4 (dd, J = 8.3, 1.9 Hz) , 1H) 7.5 (d, J = 8.1 Hz, 1H) 7.6 (m, 3H) 7.9 (d, J = 8.6 Hz, 2H) 8.0 (s, 1H) 8.4 (S, 1H) 9.4 (s, 1H) 12.9 (s, 1H). ES-LCMS m / z 434 (100), (M + H).

6- (4-Chlorophenyl) -3- {2-[(dimethylamino) methyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidin-4 (3H) -one trifluoroacetate

Step A: 2- (Chloromethyl-5-nitro-1H-benzimidazole From 2- (chloromethyl) -1H-benzimidazole (1 g, 6 mmol), concentrated HNO ₃ (2 mL) and concentrated H ₂ SO ₄ (6 mL) The resulting mixture was stirred for 30 minutes at 0 ° C. The reaction was charged with ice water (200 mL) and then extracted with EtOAc The organics were dried over MgSO ₄ (anhydrous), filtered and concentrated to dryness to give the title. Was obtained as an orange solid (940 mg, 74% yield) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.0 (s, 2H) 7.7 (d, J = 9.3 Hz) , 1H) 8.1 (dd, J = 9.0, 2.2 Hz, 1H) 8.5 (d, J = 2.4 Hz, 1H) APCI-LCMS m / z 210 (100), (M− ).

Step B: N, N-dimethyl-1- (5-nitro-1H-benzimidazol-2-yl) methanamine 2- (chloromethyl-5-nitro-1H-benzimidazole (Example 88, Step A, 940 mg, 4.44 mmol), a mixture of 2M dimethylamine in MeOH (10 mL) and MeOH (20 mL) was stirred in a pressure tube for 17 h at 100 ° C. The reaction was concentrated to dryness and the resulting crude was purified on silica gel. Purification by chromatography (0-10% MeOH / CH ₂ Cl ₂ , 30 min gradient, then 10% MeOH / CH ₂ Cl ₂ , 30 min) gave the title compound as an orange solid (350 mg, 36% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.2 (s, 6H) 3.7 ( s, 2H) 7.6 (s, 1H) 8.1 (d, J = 7.8 Hz, 1H) 8.4 (s, 1H) ES-LCMS m / z 221 (100), (M + H).

Step C: 2-[(Dimethylamino) methyl] -1H-benzimidazol-5-amine N, N-dimethyl-1- (5-nitro-1H-benzimidazol-2-yl) methanamine (Example 88, Step B, 350 mg, 1.59 mmol) was added dropwise at room temperature to a solution of Sn (II) Cl ₂ .2H ₂ O (1.26 g, 5.56 mmol) in concentrated HCl (5 mL). The mixture was stirred at room temperature for 15 minutes and then at 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature, poured onto ice, brought to pH = 8 with 10N NaOH (aq) and then concentrated to dryness. The crude residue was stirred in MeOH / CH ₂ Cl ₂ and then hot filtered. The filtrate was concentrated to dryness and the crude residue was chromatographed on silica gel (0-15% 2M ammonia in MeOH / CH ₂ Cl ₂ , 30 min gradient, then 15% 2M ammonia in MeOH / CH ₂ Cl _2. , 30 min) to give the title compound as a tan solid (160 mg, 53% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.2 (s, 6H) 3.5 (s, 2H) 6.4 (dd, J = 8.4, 2.2 Hz, 1H) 6.6 (s , 1H) 7.1 (d, J = 8.4 Hz, 1H). ES-LCMS m / z 191 (30), (M + H).

Step D: 6- (4-Chlorophenyl) -3- {2-[(dimethylamino) methyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 (3H) -ontri Fluoroacetate 2-[(dimethylamino) methyl] -1H-benzimidazol-5-amine (Example 88, Step C, 50 mg, 0.27 mmol), 5- (4-chlorophenyl) -3-{[(1E )-(Dimethylamino) methylidene] amino} -2-thiophenecarboxylate (Example 75, Step D, 271 mg, 0.84 mmol) and a mixture of phenol (2 g) was stirred at 200 ° C. for 30 minutes. The mixture was cooled to room temperature, charged with 1N NaOH (aq) (40 mL) and then extracted with CH ₂ Cl ₂ . The organics were dried over MgSO ₄ (anhydrous), filtered and the filtrate was concentrated to dryness. The resulting crude was stirred and refluxed in MeOH until homogeneous and cooled to yield a tan precipitate. The precipitate was filtered, taken up in DMSO and purified by C18 preparative HPLC (1-99% CH ₃ CN / H ₂ O, 5 min gradient) to give the title compound as a white solid (25 mg, yield 5 %). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.9 (s, 6H) 4.6 (s, 2H) 7.4 (dd, J = 8.5, 2.0 Hz, 1H) 7.6 (d , J = 8.6 Hz, 2H) 7.8 (d, J = 8.4 Hz, 1H) 7.9 (d, J = 1.9 Hz, 1H) 7.9 (d, J = 8.6 Hz, 2H) ) 8.0 (s, 1H) 8.5 (s, 1H). ES-LCMS m / z 436 (100), (M + H).

6- (4-Chlorophenyl) -3- [1-methyl-2- (1-pyrrolidinyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoro Acetate

Step A: 1-Methyl-2- (1-pyrrolidinyl) -1H-benzimidazol-5-amine 2-chloro-1-methyl-1H-benzimidazol-5-amine (Example 11, Step C, 200 mg, 1 0.1 mmol), pyrrolidine (2 mL) and EtOH (10 mL) were stirred in a pressure tube at 160 ° C. for 21.5 hours. The reaction was concentrated to dryness and the resulting crude was purified by silica gel chromatography (0-7.5% MeOH / CH ₂ Cl ₂ , 1 hour gradient) to give the title compound as a pink solid (161 mg Yield 68%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.9 (m, 4H) 3.5 (m, 4H) 3.5 (s, 3H) 6.3 (dd, J = 8.3, 2.1 Hz , 1H) 6.5 (d, J = 2.2 Hz, 1H) 6.9 (d, J = 8.4 Hz, 1H). ES-LCMS m / z 217 (100), (M + H).

Step B: 6- (4-Chlorophenyl) -3- [1-methyl-2- (1-pyrrolidinyl) -1H-benzimidazol-5-yl] thieno [3,2-d] pyrimidine-4 (3H)- Ontrifluoroacetate 1-methyl-2- (1-pyrrolidinyl) -1H-benzimidazol-5-amine (Example 89, Step A, 161 mg, 0.75 mmol), 5- (4-chlorophenyl) -3- A mixture of methyl {[(1E)-(dimethylamino) methylidene] amino} thiophenecarboxylate (Example 1, Step D, 241 mg, 0.75 mmol) and phenol (1 g) was stirred at 200 ° C. for 30 minutes. The mixture was cooled to room temperature, charged with 1N NaOH (aq) (15 mL) and extracted with CH ₂ Cl ₂ . The organics were dried over MgSO ₄ (anhydrous), filtered and the filtrate was concentrated to dryness. The resulting crude was charged with DMSO (2 mL) and EtOH (5 mL). The resulting yellow precipitate was filtered, washed with EtOH, then taken up in DMSO (3 mL) and 1 drop of TFA, and C18 preparative HPLC (1-99% CH ₃ CN / H ₂ O, 5 min gradient). ) To give the title compound as a white solid (179 mg, 41% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.0 (m, 4H) 3.8 (t, J = 6.5 Hz, 4H) 3.9 (s, 3H) 7.5 (dd, J = 8 .6, 1.9 Hz, 1H) 7.6 (m, 2H) 7.6 (d, J = 1.9 Hz, 1H) 7.7 (d, J = 8.6 Hz, 1H) 7.9 (m , 2H) 8.0 (s, 1H) 8.4 (s, 1H). ES-LCMS m / z 462 (100), (M + H).

6- (4-Chlorophenyl) -3- [1-methyl-2- (1-pyrrolidinyl) -1H-benzimidazol-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one trifluoro Acetate 2-chloro-1-methyl-1H-benzimidazol-5-amine to 2-chloro-1-methyl-1H-benzimidazol-6-amine (Example 85, Step C, 200 mg, 1.1 mmol) Instead, the title compound was synthesized using the techniques described in Example 89, Steps A and B, to give a white solid (295 mg, 51% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.9 (m, 4H) 3.4 (t, J = 6.7 Hz, 4H) 3.5 (s, 3H) 4.7 (s, 2H) 6 .3 (dd, J = 8.1, 2.3 Hz, 1H) 6.4 (d, J = 2.0 Hz, 1H) 6.9 (d, J = 8.4 Hz, 1H). ES-LCMS m / z 217 (100), (M + H).

6- (4-Chlorophenyl) -3- {2- (methylamino) -1- [3- (methyloxy) propyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 (3H) -one trifluoroacetate

Step ^A: N 1 - [3- (methyloxy) propyl] -4-nitro-1,2-benzenediamine 2-fluoro-5-nitroaniline (1g, 6.41mmol), [3- ( methyloxy) propyl A mixture of amine (571 mg, 6.41 mmol) and EtOH (10 mL) was stirred and refluxed in a pressure tube at 160 ° C. for 20 hours. The reaction was charged with [3- (methyloxy) propyl] amine (2.5 mL) and then stirred in a pressure tube at 160 ° C. for 24 hours. The mixture was concentrated and the resulting crude was purified by silica gel chromatography (CH ₂ Cl ₂ ) to give the title compound as an orange solid (350 mg, 24% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.8 (m, 2H) 3.2 (m, 5H) 3.4 (t, J = 6.1 Hz, 2H) 5.1 (s, 2H) 5 .9 (t, J = 5.2 Hz, 1H) 6.4 (d, J = 8.8 Hz, 1H) 7.4 (d, J = 2.7 Hz, 1H) 7.5 (dd, J = 8 .8, 2.7 Hz, 1 H). ES-LCMS m / z 226 (100), (M + H).

Step B: N-methyl-1- [3- (methyloxy) propyl] -5-nitro-1H-benzimidazol-2-amine N ^1- [3- (methyloxy) propyl] -4-nitro-1, A mixture of 2-benzenediamine (Example 91, Step A, 350 mg, 1.55 mmol), (methylimino) (thioxo) methane (175 mg, 2.4 mmol) and pyridine (10 mL) was stirred at 90 ° C. for 15 minutes. The mixture was cooled to room temperature and charged with 1-cyclohexyl-3- (2-morpholino-ethyl) carbodiimide nitro-p-toluenesulfonate (1.23 g, 2.91 mmol). The mixture was stirred at 90 ° C. for 3 hours. The mixture was cooled at room temperature and charged with Et ₂ O. The resulting precipitate was filtered and washed with Et ₂ O. The filtrate was concentrated to dryness and the resulting crude was chromatographed on silica gel (0-10% CH ₃ CN / CH ₂ Cl ₂ , 30 min gradient, then 10% CH ₃ CN / CH ₂ Cl ₂ , 30 min. ) To give the title compound as a yellow solid (269 mg, 66% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.8 (m, 2H) 2.9 (d, J = 4.6 Hz, 3H) 3.2 (s, 3H) 3.2 (t, J = 6 .0 Hz, 2H) 4.1 (t, J = 7.0 Hz, 2H) 7.1 (q, J = 4.6 Hz, 1H) 7.3 (d, J = 8.4 Hz, 1H) 7.9 (Dd, J = 8.7, 2.3 Hz, 1H) 8.0 (d, J = 2.4 Hz, 1H). ES-LCMS m / z 265 (100), (M + H).

Step C: N ² -Methyl-1- [3- (methyloxy) propyl] -1H-benzimidazole-2,5-diamine N-methyl-1- [3- (methyloxy) propyl] -5-nitro- A mixture of 1H-benzimidazol-2-amine (Example 91, Step B, 269 mg, 1.02 mmol), 10% Pd / C (27 mg) and MeOH (30 mL) was added under H ₂ atmosphere (1 atm). Stir for hours. The reaction was filtered through celite and the filtrate was concentrated to dryness to give the title compound as a tan solid (230 mg, 96% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ1.8 (m, 2H) 2.8 (d, J = 4.7 Hz, 3H) 3.2 (s, 3H) 3.2 (t, J = 6 .2 Hz, 2H) 3.8 (t, J = 6.9 Hz, 2H) 4.4 (s, 2H) 6.2 (m, 2H) 6.4 (d, J = 1.9 Hz, 1H) 6 .7 (d, J = 8.1 Hz, 1H). ES-LCMS m / z 235 (100), (M + H).

Step D: 6- (4-Chlorophenyl) -3- {2- (methylamino) -1- [3- (methyloxy) propyl] -1H-benzimidazol-5-yl} thieno [3,2-d] Pyrimidine-4 (3H) -one trifluoroacetate N ² -methyl-1- [3- (methyloxy) propyl] -1H-benzimidazole-2,5-diamine (Example 91, Step C, 230 mg, 0 .98 mmol), methyl 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thiophenecarboxylate (Example 1, Step D, 317 mg, 0.98 mmol) and phenol (1 g ) Was stirred at 200 ° C. for 1 hour. The mixture was cooled to room temperature, charged with 1N NaOH (aq) (10 mL) and then extracted with CH ₂ Cl ₂ . The organics were dried over MgSO (anhydrous), filtered and the filtrate was concentrated to dryness. The resulting crude was charged with DMSO (4 mL) and MeOH (20 mL). The resulting tan precipitate was filtered, washed with MeOH, then taken up in DMSO (2 mL) and 1 drop of TFA, C18 preparative HPLC (1-99% CH ₃ CN / H ₂ O, 5 min. (Gradient) gave the title compound as a white solid (45 mg, 7% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ1.9 (m, 2H) 2.5 (s, 3H) 3.1 (d, J = 4.6 Hz, 3H) 3.3 (t, J = 6 0.0 Hz, 2H) 4.2 (t, J = 6.8 Hz, 2H) 7.5 (dd, J = 8.5, 1.9 Hz, 1H) 7.6 (d, J = 8.6 Hz, 2H) ) 7.6 (d, J = 8.6 Hz, 1H) 7.7 (d, J = 1.8 Hz, 1H) 7.9 (d, J = 8.8 Hz, 2H) 8.0 (s, 1H) ) 8.4 (s, 1H) 9.0 (s, 1H). ES-LCMS m / z 480 (100), (M + H).

6- (4-Chlorophenyl) -3- (2-{[2- (methyloxy) ethyl] amino} -1H-benzimidazol-5-yl) thieno [3,2-d] pyrimidine-4 (3H)- On-trifluoroacetate salt The title compound was synthesized by using the technique described in Example 86, Steps A, B and C, replacing pyrrolidine with [2- (methyloxy) ethyl] amine (2 mL). A white solid (116 mg, 26% yield) was obtained. ¹ H NMR (300 MHz DMSO-d ₆ ) δ 3.3 (m, 3H) 3.6 (m, 4H) 7.4 (dd, J = 8.4, 1.8 Hz, 1H) 7.5 (d, J = 8.6 Hz, 1H) 7.6 (m, J = 8.6 Hz, 3H) 7.9 (d, J = 8.6 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H) 9.2 (s, 1H) 12.9 (s, 1H). ES-LCMS m / z 452 (100), (M + H).

6- (4-Chlorophenyl) -3- {2- (methylamino) -1- [2- (4-morpholinyl) ethyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine- 4 (3H) -one trifluoroacetate

Step A: N- [2- (4-morpholinyl) ethyl] -2,4-dinitroaniline [2- (4-morpholinyl) ethyl] amine (10.49 mL, 80.60 mmol) was replaced with 1-fluoro-2, To a mixture of 4-dinitrobenzene (5 g, 26.87 mmol) and EtOH (25 mL) was added at room temperature. The mixture was then stirred at 90 ° C. in a pressure tube for 15 minutes. The mixture was cooled to room temperature and the resulting precipitate was filtered, washed with EtOH and air dried to give the title compound as an orange solid (7.56 mg, 95% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.5 (m, 2H) 2.6 (t, J = 6.2 Hz, 2H) 3.6 (d, 8H) 7.2 (d, J = 9 .7 Hz, 1H) 8.3 (dd, J = 9.7, 2.8 Hz, 1H) 8.9 (d, J = 2.8 Hz, 1H) 9.1 (t, J = 4.7 Hz, 1H) ). ES-LCMS m / z 297 (90), (M + H).

Step B: A solution of N ^1- [2- (4-morpholinyl) ethyl] -4-nitro-1,2-benzenediamine Na ₂ S ₂ O ₄ (13.33 g, 76.56 mmol) in N ₂ -[2- (4-morpholinyl) ethyl] -2,4-dinitroaniline (Example 93, Step A, 7.56 g, 25.52 mmol) was added to a solution of EtOH (100 mL) at reflux. The mixture was stirred at reflux for 1.5 hours. The mixture was filtered and the filtrate was concentrated to dryness. The resulting crude was purified by silica gel chromatography (0-7.5% MeOH / CH ₂ Cl ₂ , 45 min gradient, then 10% MeOH / CH ₂ Cl ₂ , 45 min) to give the title compound Was obtained as an orange solid (2.18 g, 32% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.4 (m, 4H) 2.6 (t, J = 6.6 Hz, 2H) 3.3 (m, 2H) 3.6 (m, 4H) 5 .1 (s, 2H) 5.8 (t, J = 5.2 Hz, 1H) 6.5 (d, J = 8.8 Hz, 1H) 7.4 (d, J = 2.5 Hz, 1H) 7 .5 (dd, J = 8.8, 2.8 Hz, 1H). ES-LCMS m / z 265 (100), (M-H).

Step C: 6- (4-Chlorophenyl) -3- {2- (methylamino) -1- [2- (4-morpholinyl) ethyl] -1H-benzimidazol-5-yl} thieno [3,2-d ] Pyrimidine-4 (3H) -one trifluoroacetate N ^1- [3- (methyloxy) propyl] -4-nitro-1,2-benzenediamine was converted to N ^1- [2- (4-morpholinyl) ethyl] Instead of -4-nitro-1,2-benzenediamine (Example 93, Step B, 400 mg, 1.5 mmol), using the technique described in Example 91, Steps B, C and D, the title The compound was synthesized to give a tan solid (35 mg, 25% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.1 (s, 3H) 3.7 (s, 8H) 4.4 (s, 4H) 7.5 (d, J = 6.6 Hz, 1H) 7 .6 (d, J = 8.8 Hz, 2H) 7.7 (m, 2H) 7.9 (d, J = 8.6 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H) ). ES-LCMS m / z 522 (50), (M + H).

6- (4-Chlorophenyl) -3- {2- (dimethylamino) -1- [2- (4-morpholinyl) ethyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine- 4 (3H) -ON

Step A: N, N-dimethyl-1- [2- (4-morpholinyl) ethyl] -5-nitro-1H-benzimidazol-2-amine N ^1- [2- (4-morpholinyl) ethyl] -4- Nitro-1,2-benzenediamine (Example 93, Step B, 300 mg, 1.13 mmol), N- (dichloromethylidene) -N-methylmethanaminium chloride (551 mg, 3.39 mmol), N-ethyl- A mixture consisting of N- (1-methylethyl) -2-propanamine (1 mL) and CH ₂ Cl ₂ (10 mL) was stirred and refluxed for 2 hours. The mixture was cooled to room temperature, concentrated to dryness and the resulting crude was chromatographed on silica gel (0-8% MeOH / CH ₂ Cl ₂ , 30 min gradient, then 8% MeOH / CH ₂ Cl ₂ , 30 The title compound was obtained as a yellow oil (305 mg, 85% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.4 (m, 4H) 2.6 (t, J = 6.7 Hz, 2H) 3.0 (s, 6H) 3.4 (m, 4H) 4 .2 (t, J = 6.6 Hz, 2H) 7.6 (d, J = 8.8 Hz, 1H) 8.0 (dd, J = 8.8, 2.4 Hz, 1H) 8.1 (d , J = 2.2 Hz, 1H). ES-LCMS m / z 320 (100), (M + H).

Step ^{B: N 2,} N 2 - dimethyl-1- [2- (4-morpholinyl) ethyl]-1H-benzimidazole-2,5-diamine N, N-dimethyl-1- [2- (4-morpholinyl) Ethyl] -5-nitro-1H-benzimidazol-2-amine (Example 94, Step A, 305 mg, 0.96 mmol), a mixture of 10% Pd / C (30 mg) and MeOH (20 mL) was added to H _2. The mixture was stirred for 30 minutes under an atmosphere (1 atm). The reaction was filtered through celite and the filtrate was concentrated to dryness to give the desired compound as a pink oil (226 mg, 81% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.4 (m, 4H) 2.6 (t, J = 7.0 Hz, 2H) 2.8 (s, 6H) 3.5 (m, 4H) 4 0.0 (t, J = 7.1 Hz, 2H) 4.6 (s, 2H) 6.4 (dd, J = 8.3, 2.1 Hz, 1H) 6.6 (d, J = 2.0 Hz) , 1H) 7.0 (d, J = 8.4 Hz, 1H). ES-LCMS m / z 290 (100), (M + H).

Step C: 6- (4-Chlorophenyl) -3- {2- (dimethylamino) -1- [2- (4-morpholinyl) ethyl] -1H-benzimidazol-5-yl} thieno [3,2-d ] pyrimidin -4 (3H) - on N ^{2, N 2} - dimethyl-1- [2- (4-morpholinyl) ethyl]-1H-benzimidazole-2,5-diamine (example 94, step B, 252 mg, 0.78 mmol), methyl 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thiophenecarboxylate (Example 1, Step D, 226 mg, 0.78 mmol) and phenol ( 1 g) was stirred at 200 ° C. for 30 minutes. The mixture was cooled to room temperature and the resulting crude was chromatographed on silica gel (CH ₂ Cl ₂ , 10 min, then 0-10% MeOH / CH ₂ Cl ₂ , 30 min gradient, then 10% MeOH / CH ₂ Cl ₂ , 30 minutes). The resulting product was triturated with MeOH to give the title compound as a white solid (225 mg, 54% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.4 (m, 4H) 2.7 (t, J = 6.8 Hz, 2H) 3.0 (s, 6H) 3.5 (m, 4H) 4 .2 (t, J = 7.0 Hz, 2H) 7.2 (dd, J = 8.3, 2.1 Hz, 1H) 7.5 (m, 2H) 7.6 (d, J = 8.6 Hz) , 2H) 7.9 (d, J = 8.6 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H). ES-LCMS m / z 535 (100), (M +).

6- (4-Chlorophenyl) -3- {2-[(3S) -3-hydroxy-1-pyrrolidinyl] -1-methyl-1H-benzimidazol-6-yl} thieno [3,2-d] pyrimidine- 4 (3H) -one trifluoroacetate

Step A: (3S) -1- (6-Amino-1-methyl-1H-benzimidazol-2-yl) -3-pyrrolidinol 2-chloro-1-methyl-1H-benzimidazol-5-amine (Examples) 11, Step C, 200 mg, 1.1 mmol), a mixture consisting of (3S) -3-pyrrolidinol (444 μL) and EtOH (10 mL) was stirred in a pressure tube at 160 ° C. for 17 hours. The reaction was concentrated to dryness and the resulting crude was chromatographed on silica gel (0-10% 2M ammonia in MeOH / CH ₂ Cl ₂ , 20 min gradient, then 10% 2M ammonia in MeOH, 20 min. ) To give the title compound as a tan solid (233 mg, 91% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ1.8 (m, 1H) 2.0 (m, 1H) 3.3 (dd, J = 10.3, 1.6 Hz, 1H) 3.4 (m , 4H) 3.6 (m, 2H) 4.3 (d, J = 2.4 Hz, 1H) 4.6 (s, 2H) 4.9 (d, J = 3.4 Hz, 1H) 6.3 (Dd, J = 8.3, 2.1 Hz, 1H) 6.4 (d, J = 2.1 Hz, 1H) 6.9 (d, J = 8.3 Hz, 1H). ES-LCMS m / z 233 (100), (M + H).

Step B: 6- (4-Chlorophenyl) -3- {2-[(3S) -3-hydroxy-1-pyrrolidinyl] -1-methyl-1H-benzimidazol-6-yl} thieno [3,2-d Pyrimidine-4 (3H) -one trifluoroacetate salt (3S) -1- (6-Amino-1-methyl-1H-benzimidazol-2-yl) -3-pyrrolidinol (Example 95, Step A, 217 mg) , 0.93 mmol), methyl 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thiophenecarboxylate (Example 1, Step D, 302 mg, 0.93 mmol) and phenol The mixture consisting of (1 g) was stirred at 200 ° C. for 30 minutes. The mixture was cooled to 60 ° C. and charged with MeOH. The resulting precipitate was filtered, washed with MeOH, then taken up in DMSO and purified by C18 preparative HPLC (1-99% CH ₃ CN / H ₂ O, 5 min gradient) to give the title compound as white As a solid (91 mg, 17% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.0 (m, 2H) 3.6 (d, J = 10.1 Hz, 1H) 3.8 (s, 3H) 3.9 (m, 3H) 4 .5 (s, 1H) 5.3 (s, 1H) 7.4 (d, J = 7.9 Hz, 1H) 7.5 (m, 1H) 7.6 (d, J = 8.6 Hz, 2H) 7.9 (s, 1H) 7.9 (d, J = 8.6 Hz, 2H) 8.0 (s, 1H) 8.5 (s, 1H). ES-LCMS m / z 478 (100), (M + H).

3- [2- (Dimethylamino) -1-methyl-1H-benzimidazol-6-yl] -6- (4-fluorophenyl) thieno [3,2-d] pyrimidine-4 (3H) -one dimethanesulfone Acid salt N ² , N ² , 1-trimethyl-1H-benzimidazole-2,6-diamine (Example 11, Step D, 165 mg, 0.88 mmol), 3-{[(1E)-(dimethylamino) methylidene Amino} -5- (4-fluorophenyl) -2-thiophenecarboxylic acid (Example 3, 3-amino-5- (4-chlorophenyl) -2-thiophenecarboxylate in Step D was converted to 3-amino- Prepared by substituting 5- (4-fluorophenyl) -2-thiophenecarboxylate, a mixture consisting of 270 mg, 0.88 mmol) is phenol (1 ) Wherein at 0.99 ° C. from room temperature over 30 minutes and then stirred for 1 hour at 0.99 ° C.. The mixture was cooled to 60 ° C. and poured into MeOH. The resulting precipitate was filtered and washed with MeOH. The precipitate was taken up in CH ₂ Cl ₂ and a few drops of MeOH and then charged with methanesulfonic acid (2 eq). The mixture was concentrated to dryness and then triturated with CH ₂ Cl ₂ to give the title compound as a yellow solid (260 mg, 49% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.3 (s, 6H) 3.3 (s, 6H) 3.8 (t, 3H) 7.4 (t, J = 8.8 Hz, 2H) 7 .5 (m, 1H) 7.6 (m, 1H) 8.0 (m, 4H) 8.5 (s, 1H). ES-LCMS m / z 420 (100), (M + H).

6- (4-Chlorophenyl) -3- (1-methyl-2- {methyl [2- (1-pyrrolidinyl) ethyl] amino} -1H-benzimidazol-6-yl) thieno [3,2-d] pyrimidine -4 (3H) -one trifluoroacetate

Step A: N-methyl-2- (1-pyrrolidinyl) ethanamine 1- (2-chloroethyl) pyrrolidine (10 g, 58.8 mmol) in H ₂ O (15 mL) was added to a 40% solution of methylamine in H ₂ O. (46 mL) was added dropwise at room temperature over 30 minutes. The reaction was stirred at room temperature for 2 hours. The reaction was then further charged with a 40% methylamine solution in H ₂ O (20 mL) and stirred at room temperature for 19 hours. NaOH (18.5 g, 462.5 mmol) was added to the mixture in small portions at room temperature. The reaction was cooled to room temperature and then extracted with Et ₂ O. The organics were dried over MgSO ₄ (anhydrous), filtered, and the filtrate was concentrated to dryness to give the title compound as a golden liquid (6.64 g, 88% yield). ^{1 H NMR (300MHz, DMSO-} d 6) δ1.7 (m, 5H) 2.3 (s, 3H) 2.5 (m, 8H). ES-LCMS m / z 129 (100), (M + H).

Step ^B: N 2, 1- dimethyl ^-N 2 - [2- (1- pyrrolidinyl) ethyl]-1H-benzimidazole-2,6-diamine 2-chloro-1-methyl-1H-benzimidazol-6-amine A mixture consisting of (Example 11, Step C, 200 mg, 1.1 mmol), N-methyl-2- (1-pyrrolidinyl) ethanamine (Example 97, Step A, 282 mg, 2.2 mmol) and EtOH (10 mL). The mixture was stirred at 160 ° C. for 22 hours in a pressure tube. The reaction solution was cooled to room temperature, further charged with N-methyl-2- (1-pyrrolidinyl) ethanamine (423 mg, 3.3 mmol), and stirred at 160 ° C. for 24 hours. The reaction was concentrated to dryness and the resulting crude was purified by silica gel chromatography (10% 2M ammonia in MeOH / CH ₂ Cl ₂ ) to give the title compound as a golden oil (168 mg, 56% yield). ) Was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.6 (s, 4H) 2.5 (s, 4H) 2.6 (t, J = 7.0 Hz, 2H) 2.9 (s, 3H) 3 .3 (m, 2H) 3.3 (s, 2H) 3.5 (d, 3H) 6.4 (d, J = 8.3 Hz, 1H) 6.5 (s, 1H) 6.9 (d , J = 8.3 Hz, 1H). ES-LCMS m / z 274 (100), (M + H).

Step C: 6- (4-Chlorophenyl) -3- (1-methyl-2- {methyl [2- (1-pyrrolidinyl) ethyl] amino} -1H-benzimidazol-6-yl) thieno [3,2- d] pyrimidin -4 (3H) - one trifluoroacetic acid salt N ^2, 1-dimethyl ^-N 2 - [2- (1- pyrrolidinyl) ethyl]-1H-benzimidazole-2,6-diamine (example 97, Step B, 168 mg, 0.61 mmol), methyl 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate (Example 1, Step D, 198 mg). , 0.61 mmol) and phenol (1 g) at room temperature over 30 minutes at 150 ° C. and then stirred at 150 ° C. for 1 hour. The mixture was cooled to room temperature and then chromatographed on silica gel (CH ₂ Cl ₂ , 10 min, then 0-10% 2M ammonia in MeOH / CH ₂ Cl ₂ , 30 min gradient, then in 10% MeOH. 2M ammonia / CH ₂ Cl ₂ , 30 min). The resulting product was taken up in DMSO and purified by C18 preparative HPLC (1-99% CH ₃ CN / H ₂ O, 5 min gradient) to give the title compound as a white solid (90 mg, 23% yield). As obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.0 (s, 4H) 3.2 (s, 3H) 3.4 (s, 4H) 3.5 (t, J = 5.9 Hz, 2H) 3 .8 (m, 5H) 7.3 (dd, J = 8.3, 1.9 Hz, 1H) 7.6 (m, 3H) 7.8 (d, J = 1.9 Hz, 1H) 7.9 (D, J = 8.6 Hz, 2H) 8.0 (s, 1H) 8.5 (s, 1H). ES-LCMS m / z 519 (100), (M +).

6- (4-Chlorophenyl) -3- (1-methyl-2- {methyl [2- (1-pyrrolidinyl) ethyl] amino} -1H-benzimidazol-5-yl) thieno [3,2-d] pyrimidine -4 (3H) -one trifluoroacetate 2-chloro-1-methyl-1H-benzimidazol-6-amine was converted to 2-chloro-1-methyl-1H-benzimidazol-5-amine (Example 11, step) The title compound was synthesized using the techniques described in Example 97, Steps B and C instead of C, 200 mg, 1.1 mmol) to give a white solid (105 mg, 19% yield). It was. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.9 (s, 4H) 3.1 (s, 3H) 3.3 (s, 4H) 3.5 (t, J = 6.0 Hz, 2H) 3 .7 (m, 5H) 7.3 (dd, J = 8.4, 1.9 Hz, 1H) 7.6 (m, 4H) 7.9 (d, J = 8.6 Hz, 2H) 8.0 (S, 1H) 8.4 (s, 1H). ES-LCMS m / z 519 (100), (M +).

6- (4-Chlorophenyl) -3- (2- {methyl [2- (1-pyrrolidinyl) ethyl] amino} -1H-benzimidazol-5-yl) thieno [3,2-d] pyrimidine-4 (3H ) -Onmethanesulfonate

Step A: N-methyl-5-nitro-N- [2- (1-pyrrolidinyl) ethyl] -1H-benzimidazol-2-amine 2-chloro-5-nitro-1H-benzimidazole (Example 75, step A, 250 mg, 1.27 mmol), N-methyl-2- (1-pyrrolidinyl) ethanamine (Example 97, Step A, 244 mg, 1.91 mmol) and MeOH (10 mL) in a pressure tube at 150 ° C. For 22 hours. Concentrate the reaction to dryness and purify the resulting crude by silica gel chromatography (0-5% MeOH / CH ₂ Cl ₂ , 20 min gradient, then 5% MeOH / CH ₂ Cl ₂ , 10 min). This gave the title compound as a yellow solid (282 mg, 77% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.7 (s, 4H) 3.1 (s, 3H) 3.3 (s, 6H) 3.7 (s, 2H) 7.3 (d, J = 8.8 Hz, 1H) 7.9 (m, 2H). APCI-LCMS m / z 290 (100), (M + H).

Step B: ^{N 2} - methyl ^-N 2 - [2- (1- pyrrolidinyl) ethyl]-1H-benzimidazole-2,5-diamine N- methyl-5-nitro -N- [2- (1- pyrrolidinyl) Ethyl] -1H-benzimidazol-2-amine (Example 99, Step A, 282 mg, 0.97 mmol), a mixture of 10% Pd / C (28 mg) and EtOH (15 mL) under H ₂ atmosphere (1 atm). For 2.5 hours. The reaction was filtered through celite and the filtrate was concentrated to dryness to give the title compound as a brown solid (247 mg, 98% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.7 (m, 4H) 2.7 (m, J = 5.5, 5.5 Hz, 4H) 2.8 (t, J = 6.5 Hz, 2H) ) 3.0 (s, 3H) 3.6 (t, J = 6.6 Hz, 2H) 6.2 (dd, J = 8.3, 1.9 Hz, 1H) 6.5 (d, J = 1) .9 Hz, 1H) 6.8 (d, J = 8.3 Hz, 1H). ES-LCMS m / z 260 (100), (M + H).

Step C: 6- (4-Chlorophenyl) -3- (2- {methyl [2- (1-pyrrolidinyl) ethyl] amino} -1H-benzimidazol-5-yl) thieno [3,2-d] pyrimidine- 4 (3H) - on methanesulfonate N ² - methyl ^-N 2 - [2- (1- pyrrolidinyl) ethyl]-1H-benzimidazole-2,5-diamine (example 99, step B, 226 mg, 0 .87 mmol), methyl 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate (Example 1, Step D, 282 mg, 0.87 mmol) and A mixture of phenol (1 g) was stirred from room temperature to 120 ° C. over 30 minutes and then at 120 ° C. for 30 minutes. The mixture was cooled to room temperature and then purified by silica gel chromatography (CH ₂ Cl ₂ , 10 min, then 0-10% 2M ammonia in MeOH / CH ₂ Cl ₂ , 30 min gradient). The resulting product was taken up in CH ₂ Cl ₂ and charged with methanesulfonic acid (19 μL). The resulting precipitate was filtered, washed with CH ₂ Cl ₂ and dried under high vacuum to give the title compound as an off-white solid (60 mg, 20% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.0 (s, 4H) 2.4 (s, 6H) 3.3 (s, 3H) 3.6 (t, J = 5.2 Hz, 2H) 3 7 (s, 4H) 4.0 (t, J = 5.5 Hz, 2H) 7.4 (d, J = 8.6 Hz, 1H) 7.6 (d, J = 8.6 Hz, 3H) 7 7 (s, 1H) 8.0 (d, J = 8.6 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H). APCI-LCMS m / z 505 (100), (M +).

6- (4-Chlorophenyl) -3- {2- (dimethylamino) -1- [2- (dimethylamino) ethyl] -1H-benzimidazol-6-yl} thieno [3,2-d] pyrimidine-4 (3H) -Onmethanesulfonate

Step A: N, N-dimethyl-5-nitro-1H-benzimidazol-2-amine 2-chloro-5-nitro-1H-benzimidazole (Example 75, Step A, 1 g, 5.06 mmol) and in MeOH A mixture of 2M dimethylamine (10 mL) was stirred at 160 ° C. in a pressure tube for 1 hour. The reaction was concentrated to dryness and the resulting crude was purified by silica gel chromatography (0-5% MeOH / CH ₂ Cl ₂ , 30 min gradient, 5% MeOH / CH ₂ Cl ₂ , 30 min). The title compound was a yellow solid (846 mg, 81% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.1 (s, 6H) 7.2 (d, J = 9.0 Hz, 1H) 7.9 (m, J = 9.7 Hz, 2H) 11.8 (S, 1H). ES-LCMS m / z 207 (100), (M + H).

Step B: [2- (Dimethylamino) -6-nitro-1H-benzimidazol-1-yl] methyl acetate NaH (1.26 g, 31.53 mmol) was added to N, N-dimethyl-5-nitro-1H- To a solution of benzimidazol-2-amine (Example 100, Step A, 5 g, 24.25 mmol) in DMF (50 mL) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction was charged with methyl bromoacetate (2.52 mL, 26.67 mmol) and stirred at room temperature for 16 hours. The reaction is concentrated to dryness and the resulting residue is chromatographed on silica gel (0-4% MeOH / CH ₂ Cl ₂ , 30 min gradient, then 4% MeOH / CH ₂ Cl ₂ , 30 min). Purified. The resulting compound was separated by chiral preparative HPLC chromatography to give the title compound as a yellow solid (2.5 g, 37% yield). ¹ H NMR (400 MHz DMSO-d ₆ ) δ 3.0 (s, 6H) 3.7 (s, 3H) 5.2 (s, 2H) 7.4 (d, J = 8.8 Hz, 1H) 0 (d, J = 11.0 Hz, 1H) 8.3 (d, J = 2.1 Hz, 1H). APCI-LCMS m / z 279 (100), (M + H).

Step C: 2- [2- (Dimethylamino) -6-nitro-1H-benzimidazol-1-yl] -N, N-dimethylacetamide [2- (Dimethylamino) -6-nitro-1H-benzimidazole- 1-yl] methyl acetate (Example 100, Step B, 300 mg, 1.08 mmol) and 2M dimethylamine in MeOH (10 mL) at 120 ° C. for 30 minutes in a pressure tube, then 19.5 at 80 ° C. Stir for hours. The reaction solution was cooled to room temperature, and the resulting precipitate was filtered off. The filtrate was concentrated to dryness and the resulting crude was purified by silica gel chromatography (0-5% MeOH / CH ₂ Cl ₂ , 20 min gradient) to give the title compound as a yellow solid (180 mg, yield 51 %). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.9 (s, 3H) 3.0 (s, 6H) 3.1 (s, 3H) 5.2 (s, 2H) 7.4 (d, J = 8.8 Hz, 1H) 8.0 (d, J = 8.8 Hz, 1H) 8.1 (s, 1H). ES-LCMS m / z 292 (100), (M + H).

Step D: 1- [2- (Dimethylamino) ethyl] -N, N-dimethyl-6-nitro-1H-benzimidazol-2-amine AlH ₃ (1M) in THF (3.1 mL, 3.1 mmol) Of 2- [2- (dimethylamino) -6-nitro-1H-benzimidazol-1-yl] -N, N-dimethylacetamide (Example 100, Step C, 180 mg, 0.62 mmol) in THF (10 mL). ) The suspension was added dropwise at 0 ° C. The reaction was stirred at room temperature for 1 hour. The reaction was poured into 1N NaOH (aq) at 0 ° C. and then extracted with CH ₂ Cl ₂ . The organics were dried over MgSO ₄ (anhydrous), filtered and concentrated to dryness. The resulting residue was purified by silica gel chromatography (0-5% 2M ammonia in MeOH, 15 min gradient, then 5% 2M ammonia in MeOH / CH ₂ Cl ₂ , 15 min) to give the title compound Was obtained as a yellow oil (95 mg, 55% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.2 (s, 6H) 2.6 (t, J = 6.6 Hz, 2H) 3.1 (s, 6H) 4.3 (t, J = 6 .6 Hz, 2H) 7.4 (d, J = 8.8 Hz, 1H) 8.0 (dd, J = 8.8, 2.2 Hz, 1H) 8.3 (s, 1H). ES-LCMS m / z 278 (100), (M + H).

Step E: 1- [2- (dimethylamino) ^ethyl] -N ^{2, N} 2 - dimethyl -1H- benzimidazole-2,6-diamine 1- [2- (dimethylamino) ethyl] -N, N-dimethyl 6-nitro -1H- benzimidazol-2-amine (example 100, step D, 92 mg, 0.33 mmol), a mixture of 10% Pd / C (10mg) and EtOH (10 mL), the atmosphere of _{H 2} The mixture was stirred for 30 minutes under (1 atm). The reaction was filtered through celite and the filtrate was concentrated to dryness to give the title compound as a golden oil (77 mg, 94% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.2 (s, 6H) 2.6 (t, J = 7.3 Hz, 2H) 2.8 (s, 6H) 4.0 (m, 2H) 4 .8 (s, 2H) 6.4 (dd, J = 8.3, 2.1 Hz, 1H) 6.5 (s, 1H) 7.0 (d, J = 8.4 Hz, 1H). ES-LCMS m / z 248 (100), (M + H).

Step F: 6- (4-Chlorophenyl) -3- {2- (dimethylamino) -1- [2- (dimethylamino) ethyl] -1H-benzimidazol-6-yl} thieno [3,2-d] Pyrimidine-4 (3H) -one methanesulfonate 1- [2- (dimethylamino) ethyl] -N ² , N ² -dimethyl-1H-benzimidazole-2,6-diamine (Example 100, Step E, 77 mg, 0.31 mmol), methyl 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate (Example 1, Step D, 100 mg,. 31 mmol) and phenol (1 g) was stirred from room temperature to 120 ° C. over 30 minutes and then stirred at 120 ° C. for 30 minutes. The mixture was cooled to room temperature and then purified by silica gel chromatography (CH ₂ Cl ₂ , 15 min, then 0-10% 2M ammonia in MeOH, 30 min gradient). The resulting product was taken up in CH ₂ Cl ₂ and charged with methanesulfonic acid (18 μL). The solution was charged with Et ₂ O and the resulting precipitate was filtered, washed with Et ₂ O and air dried to give the title compound as an off-white solid (28 mg, 13% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.3 (s, 6H) 2.9 (m, J = 4.5 Hz, 6H) 3.6 (m, 2H) 3.7 (s, 6H) 4 .6 (m, 2H) 7.5 (d, J = 8.1 Hz, 1H) 7.6 (m, 3H) 7.9 (m, 3H) 8.0 (s, 1H) 8.5 (s , 1H). APCI-LCMS m / z 492 (100), (M-H).

6- (4-Chlorophenyl) -3- (1-methyl-2- {methyl [2- (methyloxy) ethyl] amino} -1H-benzimidazol-5-yl) thieno [3,2-d] pyrimidine- 4 (3H) -one dimethanesulfonate

Step ^A: N 2, 1- dimethyl ^-N 2 - [2- (methyloxy) ethyl]-1H-benzimidazole-2,5-diamine 2-chloro-1-methyl-1H-benzimidazol-5-amine ( A mixture consisting of Example 11, Step C, 200 mg, 1.1 mmol), N-methyl-2- (methyloxy) ethanamine (1.2 mL, 11 mmol) and EtOH (10 mL) in a pressure tube at 160 ° C. for 25 hours. Stir. The reaction was further charged with N-methyl-2- (methyloxy) ethanamine (0.6 mL, 5.5 mmol) and stirred in a pressure tube at 160 ° C. for 24 hours. The reaction was concentrated to dryness and the resulting crude was purified by silica gel chromatography (0-5% 2M ammonia in MeOH / CH ₂ Cl ₂ , 20 min gradient) to give the title compound as a brown oil ( 218 mg, 85% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.9 (s, 3H) 3.3 (s, 3H) 3.3 (m, 2H) 3.5 (s, 3H) 3.6 (t, J = 5.7 Hz, 2H) 4.6 (s, 2H) 6.4 (dd, J = 8.3, 1.9 Hz, 1H) 6.6 (d, J = 1.9 Hz, 1H) 6.9 (D, J = 8.3 Hz, 1H). ES-LCMS m / z 235 (100), (M + H).

Step B: 6- (4-Chlorophenyl) -3- (1-methyl-2- {methyl [2- (methyloxy) ethyl] amino} -1H-benzimidazol-5-yl) thieno [3,2-d ] pyrimidin -4 (3H) - Onji methanesulfonate N ^2, 1-dimethyl ^-N 2 - [2- (methyloxy) ethyl]-1H-benzimidazole-2,5-diamine (example 101, step A 218 mg, 0.93 mmol), methyl 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate (Example 1, Step D, 300 mg, 0 .93 mmol) and phenol (1 g) at room temperature over 30 minutes at 120 ° C. and then stirred at 120 ° C. for 1 hour. The reaction was cooled to 60 ° C., poured into MeOH, the resulting precipitate was filtered, washed with MeOH and air dried. The precipitate was taken up in 3 drops of DMSO and TFA and purified by C18 preparative HPLC (1-99% CH ₃ CN / H ₂ O, 5 min gradient). The resulting compound was purified by silica gel chromatography (CH ₂ Cl ₂ , 5 min, then 0-5% 2M ammonia in MeOH, 20 min gradient). The resulting compound was taken up in CH ₂ Cl ₂ and treated with methanesulfonic acid (0.03 mL). The mixture was concentrated to dryness to give the title compound as a white solid (145 mg, 23% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.3 (s, 6H) 3.3 (s, 3H) 3.3 (s, 3H) 3.7 (t, J = 5.0 Hz, 2H) 3 .8 (t, J = 5.0 Hz, 2H) 3.9 (s, 3H) 7.6 (m, 3H) 7.7 (d, J = 1.7 Hz, 1H) 7.8 (d, J = 8.6 Hz, 1H) 8.0 (d, J = 8.6 Hz, 2H) 8.0 (s, 1H) 8.5 (s, 1H). ES-LCMS m / z 480 (100), (M + H).

6- (4-Chlorophenyl) -3- {2-[(3-hydroxypropyl) (methyl) amino] -1-methyl-1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 (3H) -Ondimethanesulfonate

Step A: N ¹ -Methyl-4-nitro-1,2-benzenediamine 2-Fluoro-5-nitroaniline (10 g, 6.41 mmol) in MeOH (50 mL) was added to 2 M dimethylamine solution in MeOH (100 mL). ) Was added dropwise at room temperature. The reaction was stirred in a pressure tube at 140 ° C. for 8 hours and then at room temperature for 70 hours. The reaction was cooled to room temperature, concentrated, and the resulting crude was purified by silica gel chromatography (CH ₂ Cl ₂ ) to give the title compound as a red solid (7.6 g, 71% yield). . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ2.8 (d, J = 5.0 Hz, 3H) 5.1 (s, 2H) 6.1 (d, J = 4.7 Hz, 1H) 6.4 (D, J = 9.1 Hz, 1H) 7.4 (d, J = 2.5 Hz, 1H) 7.6 (dd, J = 8.8, 2.5 Hz, 1H). ES-LCMS m / z 166 (100), (M-H).

Step B: N, 1-Dimethyl-5-nitro-1H-benzimidazol-2-amine N ¹ -methyl-4-nitro-1,2-benzenediamine (Example 102, Step A, 5 g, 29.9 mmol) , (Methylimino) (thioxo) methane (2.34 g, 32.0 mmol) and pyridine (40 mL) were stirred at 90 ° C. for 5 minutes. The mixture was cooled to room temperature and charged with 1-cyclohexyl-3- (2-morpholino-ethyl) carbodiimide nitro-p-toluenesulfonate (16.48 g, 38.9 mmol). The mixture was stirred at 90 ° C. for 3 hours, cooled to room temperature and then charged with Et ₂ O. The resulting precipitate was stirred in EtOAc (300 mL), filtered and washed with EtOAc. The precipitate was stirred in MeOH at room temperature for 12 hours, filtered, and the MeOH filtrate was concentrated to dryness. The resulting crude filtrate was purified by silica gel chromatography (0-20% CH ₃ CN / CH ₂ Cl ₂ , 90 min gradient) to give the title compound as an orange solid (4 g, 69% yield). It was. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.0 (d, J = 4.7 Hz, 3H) 3.6 (s, 3H) 7.2 (q, J = 4.4 Hz, 1H) 7.3 (D, J = 8.8 Hz, 1H) 7.9 (dd, J = 8.8, 2.2 Hz, 1H) 8.0 (d, J = 2.2 Hz, 1H). ES-LCMS m / z MS 207 (100), (M + H).

Step C: N, 1-Dimethyl-5-nitro-N- {3-[(phenylmethyl) oxy] propyl} -1H-benzimidazol-2-amine NaH (48 mg, 1.2 mmol) was added to N, 1- To a solution of dimethyl-5-nitro-1H-benzimidazol-2-amine (Example 102, Step B, 206 mg, 1.0 mmol) in DMF (5 mL) was added at 0 ° C. The mixture was stirred at 0 ° C. for 15 minutes and {[(3-bromopropyl) oxy] methyl} benzene (177 μL, 1.0 mmol) was added dropwise at 0 ° C. The reaction was stirred at room temperature for 2 hours, quenched with MeOH and then concentrated to dryness. The resulting crude was purified by silica gel chromatography (CH ₂ Cl ₂ ) to give the title compound as a yellow oil (280 mg, 79% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.9 (m, 2H) 3.0 (s, 3H) 3.5 (m, 4H) 3.7 (s, 3H) 4.4 (s, 2H ) 7.3 (m, 5H) 7.5 (d, J = 8.8 Hz, 1H) 8.0 (dd, J = 8.7, 2.3 Hz, 1H) 8.2 (d, J = 2) .2Hz, 1H). ES-LCMS m / z 354 (100), (M + 2H).

Step D: 3-[(5-Amino-1-methyl-1H-benzimidazol-2-yl) (methyl) amino] -1-propanol N, 1-dimethyl-5-nitro-N- {3-[( Phenylmethyl) oxy] propyl} -1H-benzimidazol-2-amine (Example 102, Step C, 280 mg, 0.79 mmol), a mixture of 10% Pd / C (28 mg) and EtOH (20 mL) was added to H _2. Stir for 42 hours under 40 psi. The reaction was filtered through celite and fresh Pd / C (50 mg) was added. The reaction was stirred for 72 hours under _H 2 55 psi. The reaction was charged with 10% Pd / C (50 mg) and stirred under H ₂ 55 psi for 28.5 hours. The reaction was filtered through celite and the filtrate was concentrated to dryness to give the title compound as a pale oil (164 mg, 89% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.7 (m, 2H) 2.9 (s, 3H) 3.3 (m, 2H) 3.4 (t, J = 6.2 Hz, 2H) 3 .5 (s, 3H) 4.9 (s, 2H) 6.4 (dd, J = 8.3, 2.2 Hz, 1H) 6.6 (d, J = 1.9 Hz, 1H) 7.0 (D, J = 8.3 Hz, 1H). ES-LCMS m / z 236 (100), (M + 2H).

Step E: 6- (4-Chlorophenyl) -3- (1-methyl-2- {methyl [2- (1-pyrrolidinyl) ethyl] amino} -1H-benzimidazol-5-yl) thieno [3,2- d] Pyrimidine-4 (3H) -one trifluoroacetate salt 3-[(5-Amino-1-methyl-1H-benzimidazol-2-yl) (methyl) amino] -1-propanol (Example 102, step D, 164 mg, 0.7 mmol), methyl 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate (Example 1, Step D, 226 mg, 0.7 mmol) and phenol (1 g) was stirred from room temperature to 130 ° C. over 15 minutes and then stirred at 130 ° C. for 1 hour. The mixture was cooled to room temperature and then purified by silica gel chromatography (0-5% MeOH / CH ₂ Cl ₂ , 30 min, then 5% MeOH / CH ₂ Cl ₂ , 10 min gradient). The resulting product was taken up in CH ₂ Cl ₂ and charged into methanesulfonic acid (38 μL), then concentrated to dryness to give the title compound as a tan solid (86 mg, 18% yield). . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.8 (m, 2H) 2.3 (s, 6H) 3.3 (s, 3H) 3.5 (t, J = 5.8 Hz, 2H) 3 .7 (t, J = 7.0 Hz, 2H) 3.8 (s, 3H) 7.5 (dd, J = 8.6, 1.6 Hz, 1H) 7.6 (d, J = 8.6 Hz) , 2H) 7.7 (s, 1H) 7.8 (d, J = 8.8 Hz, 2H) 7.9 (d, J = 8.6 Hz, 2H) 8.0 (s, 1H) 8.4 (S, 1H). ES-LCMS m / z 400 (100), (M + H).

6- (4-Chlorophenyl) -3- (2-{[4- (4-fluorophenyl) piperidin-1-yl] methyl} quinolin-6-yl) thieno [3,2-d] pyrimidine-4 (3H )-ON

Step A: 2-{[4- (4-Fluorophenyl) piperidin-1-yl] methyl} -6-nitroquinoline Using an experimental procedure similar to that in Example 2, Step B, 2- (bromomethyl) 2-{[4- (4-fluorophenyl) piperidin-1-yl] methyl} -6-nitroquinoline was prepared by reacting -6-nitroquinoline with 4- (4-fluorophenyl) piperidine. . The desired compound was purified by column chromatography on silica gel eluting with a 70% ethyl acetate in hexane gradient. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.09 (s, 1H), 8.74 (d, J = 8.6 Hz, 1H), 8.50 (d, J = 9.8 Hz, 1H), 8.22 (d, J = 9.3 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.35 to 7.10 (m, 4H), 3.89 (s, 2H) ), 3.65 (m, 1H), 3.21 (m, 2H), 2.97 (m, 2H), 1.87 (m, 4H); ES-LCMS m / z 366 (M + H).

Step B: 2-{[4- (4-Fluorophenyl) piperidin-1-yl] methyl} quinolin-6-amine Using the same experimental procedure as in Example 2, Step C, 2-{[4 Reduction of-(4-fluorophenyl) piperidin-1-yl] methyl} -6-nitroquinoline with hydrogen gas and 10% Pd / C yields 2-{[4- (4-fluorophenyl) Piperidin-1-yl] methyl} quinolin-6-amine was prepared. The crude compound was used as such in the next step. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.97 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8 .9 Hz, 1H), 7.63 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.33 to 7.10 (m, 4H), 5.59 (brs, 2H) ) 3.89 (s, 2H), 3.62 (m, 1H), 3.37 (m, 2H), 2.98 (m, 2H), 2.64 (m, 2H), 1.86 ( m, 2H); ES-LCMS 336 m / z (M + H).

Step C: 6- (4-Chlorophenyl) -3- (2-{[4- (4-fluorophenyl) piperidin-1-yl] methyl} quinolin-6-yl) thieno [3,2-d] pyrimidine- 4 (3H) -one Using the same experimental procedure as in Example 2, Step D, 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thiophene-2 -Methyl carboxylate (Example 1, Step D) is reacted with 2-{[4- (4-Fluorophenyl) piperidin-1-yl] methyl} quinolin-6-amine (Example 4, Step B). The title compound was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.66 (s, 1H), 8.36 (s, 1H), 8.29 (d, J = 9.0 Hz, 1H), 8.07-7. 91 (m, 8H), 7.65 (d, J = 8.7 Hz, 1H), 7.33 (m, 1H), 7.17 (m, 2H), 3.87 (s, 2H), 3 .04 (m, 3H), 2.80 (m, 2H), 2.26 (m, 2H), 1.84 (m, 2H); ES-LCMS m / z 581 (M + H).

6- (4-Chlorophenyl) -3- [2-({4- [4- (trifluoromethyl) phenyl] piperidin-1-yl} methyl) quinolin-6-yl] thieno [3,2-d] pyrimidine -4 (3H) -ON

Step A: 6-Nitro-2-({4- [4- (trifluoromethyl) phenyl] piperidin-1-yl} methyl) quinoline 2 using the same experimental procedure as in Example 2, Step B By reacting-(bromomethyl) -6-nitroquinoline with 4- (4-fluorophenyl) piperidine, 6-nitro-2-({4- [4- (trifluoromethyl) phenyl] piperidine-1- Il} methyl) quinoline was prepared. The desired compound was purified by column chromatography on silica gel eluting with a gradient of 70% ethyl acetate in hexane. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.09 (s, 1H), 8.75 (d, J = 8.6 Hz, 1H), 8.50 (d, J = 9.3 Hz, 1H), 8.23 (d, J = 9.3 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.35-7 .10 (d, J = 8.1 Hz, 2H), 3.90 (s, 2H), 3.68 (m, 1H), 3.23 (m, 2H), 2.98 (m, 2H), 1.87 (m, 4H); ES-LCMS m / z 416 (M + H).

Step B: 2-({4- [4- (trifluoromethyl) phenyl] piperidin-1-yl} methyl) quinolin-6-amine 6 using the same experimental procedure as in Example 2, Step C. -Nitro-2-({4- [4- (trifluoromethyl) phenyl] piperidin-1-yl} methyl) quinoline is reduced with hydrogen gas and 10% Pd / C to give 2-({4 -[4- (Trifluoromethyl) phenyl] piperidin-1-yl} methyl) quinolin-6-amine was prepared. The crude compound was used as such in the next step. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.97 (d, J = 8.6 Hz, 1H), 7.73 (m, 3H), 7.69 (m, 3H), 7.16 (m, 1H)), 5.60 (brs, 2H), 3.91 (s, 2H), 3.64 (m, 1H), 3.38 (m, 2H), 3.01 (m, 2H), 2 .61 (m, 3H), 1.89 (m, 2H); ES-LCMS m / z 386 (M + H).

Step C: 6- (4-Chlorophenyl) -3- [2-({4- [4- (trifluoromethyl) phenyl] piperidin-1-yl} methyl) quinolin-6-yl] thieno [3,2- d] pyrimidin-4 (3H) -one Using the same experimental procedure as in Example 2, Step D, 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino } Methyl thiophenecarboxylate (Example 1, Step D) and 2-({4- [4- (trifluoromethyl) phenyl] piperidin-1-yl] methyl} quinolin-6-amine (Example 4, Step B) ) were reacted to prepare the title ^{compound. 1 H NMR (300MHz, DMSO} -d 6) δ8.62 (s, 1H), 8.48 (d, J = 8.6Hz, 1H) 8.24 (s, 1H), 8.18 (d, J = 9.0 Hz, 1H), 8.11 to 7.81 (m, 8H), 7.83 (d, J = 8.6 Hz, 1H) ), 7.70-7.38 (m, 2H), 3.89 (s, 2H), 3.03 (m, 3H), 2.75 (m, 2H), 2.24 (m, 2H) 1.81 (m, 2H); ES-LCMS m / z 631 (M + H).

6- (4-Chlorophenyl) -3- [2- (piperidin-1-ylmethyl) quinolin-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: 6-Nitro-2- (piperidin-1-ylmethyl) quinoline React 2- (bromomethyl) -6-nitroquinoline with piperidine using the same experimental procedure as in Example 2, Step B. Thus, 6-nitro-2- (piperidin-1-ylmethyl) quinoline was prepared. The desired compound was purified by column chromatography on silica gel eluting with a gradient of 70% ethyl acetate in hexane. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.07 (s, 1H), 8.70 (d, J = 8.7 Hz, 1H), 8.48 (d, J = 9.3 Hz, 1H), 8.20 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 3.80 (s, 2H), 2.53 (m, 4H), 1. 60-1.43 (m, 6H); ES-LCMS m / z 272 (M + H).

Step B: 2- (Piperidin-1-ylmethyl) quinolin-6-amine Using the same experimental procedure as in Example 2, Step C, hydrogenate 6-nitro-2- (piperidin-1-ylmethyl) quinoline with hydrogen. 2- (Piperidin-1-ylmethyl) quinolin-6-amine was prepared by reduction with gas and 10% Pd / C. The crude compound was used as such in the next step. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.92 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8 .4 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1 H), 5.52 (brs, 2H) 3.60 (s, 2H), 2.54 (m, 4H), 1.56 ~ 1.41 (m, 6H); ES-LCMS m / z 242 (M + H).

Step C: 6- (4-Chlorophenyl) -3- [2- (piperidin-1-ylmethyl) quinolin-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one Example 2, Step Using the same experimental procedure as in D, methyl 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thiophene-2-carboxylate (Example 1, Step D ) And 2- (piperidin-1-ylmethyl) quinolin-6-amine (Example 105, Step B) to prepare the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.64 (s, 1H), 8.63 (d, J = 9.1 Hz, 1H), 8.36 (s, 1H), 8.28 (d, J = 9.0 Hz, 1H), 8.07 (m, 5H), 7.65 (m, 2H), 3.50 (s, 2H), 2.53 (m, 4H), 1.86-1 .49 (m, 6H); ES-LCMS m / z 487 (M + H).

6- (4-Chlorophenyl) -3- [2- (piperidin-1-ylmethyl) -1-benzothien-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: Methyl 5-nitro-1-benzothiophene-2-carboxylate In a DMF (60 mL) solution consisting of 5.55 g (30 mmol) 2-chloro-5-nitrobenzaldehyde and 2.68 mL (30 mmol) methyl mercaptoacetate, KOH (3.0 g) in 15 mL of water was added dropwise. After stirring for 1 hour, the contents were poured onto crushed ice and the solid was filtered, washed with water and dried. The crude product was transferred directly to the next step. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.96 (s, 1 H), 8.40 (s, 1 H), 8.36 (s, 1 H), 8.34 (d, J = 7.8 Hz, 1H), 8.36 (d, J = 7.8 Hz, 1H), 3.90 (s, 3H); ES-LCMS m / z 238 (M + H).

Step B: 5-Nitro-1-benzothiophene-2-carboxylic acid 14.0 g (60 mmol) of methyl 5-nitro-1-benzothiophene-2-carboxylate obtained in Step A was added to a THF (60 mL) solution. 60 mL of 1N LiOH was added and the contents were stirred for 16 hours. After acidification, ethyl acetate (100 mL) was added and the organic layer was separated. The organic layer was dried with MgSO ₄ and then concentrated to give the acid in quantitative yield. ^{1 H NMR (300MHz, DMSO-} d 6) δ8.97 (s, 1H), 8.40 (m, 4H); ES-LCMS m / z 223 (M + H).

Step C: 1-[(5-Nitro-1-benzothien-2-yl) carbonyl] piperidine 5-Nitro-1-benzothiophene-2-carboxylic acid (1.3 g, 5.83 mmol) obtained in Step B To a DCM (30 mL) solution is added Hunig's base 1.21 mL (6.99 mmol), EDC (1.23 g, 6.41 mmol), HOBT (6.99 mmol) and piperidine (0.633 mL, 6.41 mmol), The contents were stirred at room temperature for 16 hours. After washing with saturated sodium chloride solution followed by saturated NaHCO ₃ solution, the organic layer was dried with MgSO ₄ and concentrated to give the desired product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 8.36 (d, J = 9.0 Hz, 1H), 8.28 (d, J = 9.0 Hz, 1H), 7.97 (s, 1H), 3.68 (m, 4H), 1.69 (m, 6H); ES-LCMS m / z 291 (M + H).

Step D: 2- (Piperidin-1-ylcarbonyl) -1-benzothien-5-ylamine of 1-[(5-nitro-1-benzothien-2-yl) carbonyl] piperidine (1.6 g, 5.80 mmol) in methanol (30 mL) solution, 10% Pd / C a (0.13 g) was added, maintaining the contents under _{H 2} to 40 psi. After 4 hours, the solution was filtered through celite and then concentrated in vacuo to give the amine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.63 (d, J = 8.7 Hz, 1H), 7.46 (s, 1H), 7.01 (s, 1H), 6.83 (d, J = 8.6 Hz, 1H), 5.20 (brs, 2H), 3.36 (m, 4H), 1.68 (m, 6H); ES-LCMS m / z 261 (M + H).

Step E: 2- (Piperidin-1-ylmethyl) -1-benzothiophen-5-amine 2- (piperidin-1-ylcarbonyl) -1-benzothien-5-ylamine (1.0 g, 3.85 mmol) in THF To the (20 mL) solution was added 1.0 M LAH solution in THF (19.2 mL, 19.2 mmol) and the contents were refluxed for 20 hours. After adding 1N sodium hydroxide, ethyl acetate was added and the organic layer was separated. Drying (MgSO ₄ ) and concentration afforded the desired product, which was taken as such to the next step. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.50 (d, J = 8.6 Hz, 1 H), 7.46 (s, 1 H), 7.0 (s, 1 H), 6.88 (d, J = 8.6 Hz, 1H), 5.02 (brs, 2H), 3.66 (s, 2H), 2.54 (m, 4H), 1.54 (m, 6H); ES-LCMS m / z 247 (M + H).

Step F: 6- (4-Chlorophenyl) -3- [2- (piperidin-1-ylmethyl) -1-benzothien-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one 2. Using a similar experimental procedure as in Step D, 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thiophene-2-carboxylate (Example 1, The title compound was prepared by reacting Step D) with 2- (piperidin-1-ylmethyl) -1-benzothiophen-5-amine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.54 (s, 1H), 8.28 (m, 2H), 8.05 (m, 3H), 8.00 (d, J = 8.6 Hz, 1H), 7.82 (s, 1H), 7.64 (m, 2H), 3.81 (s, 2H), 2.48 (m, 4H), 1.65 (m, 6H); ES- LCMS m / z 492 (M + H).

6- (4-Chlorophenyl) -3- [2- (morpholin-4-ylmethyl) -1-benzothien-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: 4-[(5-Nitro-1-benzothien-2-yl) carbonyl] morpholine Using an experimental procedure similar to that in Example 106, Step C, 5-nitro-1-benzothiophene-2- 4-[(5-Nitro-1-benzothien-2-yl) carbonyl] morpholine was prepared by reacting carboxylic acid with morpholine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 8.32 (d, J = 9.0 Hz, 1H), 8.25 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 3.67 (m, 8H); ES-LCMS m / z 293 (M + H).

Step B: 2- (morpholin-4-ylcarbonyl) -1-benzothien-5-ylamine Using an experimental procedure similar to that in Example 106, Step D, 4-[(5-nitro-1-benzothien- 2- (morpholin-4-ylcarbonyl) -1-benzothien-5-ylamine was prepared by reducing 2-yl) carbonyl] morpholine with hydrogen gas and Pd / C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.47 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 6.83 (s, 1H), 6.63 (d, J = 8.4 Hz, 1H), 5.23 (brs, 2H), 3.34 (m, 8H); ES-LCMS m / z 263 (M + H).

Step C: 2- (morpholin-4-ylmethyl) -1-benzothiophen-5-amine Using the same experimental procedure as in Example 106, Step E, 2- (morpholin-4-ylcarbonyl) -1 -2- (morpholin-4-ylmethyl) -1-benzothiophen-5-amine was prepared by reducing benzothien-5-ylamine with LAH. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.48 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 6.81 (s, 1H), 6.64 (d, J = 8.4 Hz, 1H), 5.0 (brs, 2H), 3.57 (t, J = 4.6 Hz, 4H), 2.49 (m, 4H); ES-LCMS m / z 249 ( M + H).

Step D: 6- (4-Chlorophenyl) -3- [2- (morpholin-4-ylmethyl) -1-benzothien-5-yl] thieno [3,2-d] pyrimidin-4 (3H) -one 2, Using the same experimental procedure as in Step D, 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thiophene-2-carboxylate (Example 1, The title compound was prepared by reacting Step D) with 2- (morpholin-4-ylmethyl) -1-benzothiophen-5-amine (Example 107, Step C). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.48 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.98 (m, 3H), 7.58 (d, J = 8.6 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.38 (s, 1H), 7.16 (m, 1H) 3.81 (s, 2H), 3.60 (m, 4H) 2.49 (m, 4H); ES-LCMS m / z 494 (M + H).

6- (4-Chlorophenyl) -3- {2-[(4-phenylpiperidin-1-yl) methyl] -1-benzothien-5-yl} thieno [3,2-d] pyrimidine-4 (3H)- on

Step A: 1-[(5-Nitro-1-benzothien-2-yl) carbonyl] -4-phenylpiperidine Using an experimental procedure similar to that in Example 106, Step C, 5-nitro-1-benzo 1-[(5-Nitro-1-benzothien-2-yl) carbonyl] -4-phenylpiperidine was prepared by reacting thiophene-2-carboxylic acid with 4-phenylpiperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 8.37 (d, J = 8.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.05 (s, 1H), 7.26 (m, 5H), 3.19 (m, 2H), 2.92 (m, 3H), 1.89 (m, 4H); ES-LCMS m / z 367 (M + H).

Step B: 2-[(4-Phenylpiperidin-1-yl) carbonyl] -1-benzothiophen-5-amine Using the same experimental procedure as in Example 106, Step D, 1-[(5- 2-[(4-phenylpiperidin-1-yl) carbonyl] -1-benzothiophene by reducing nitro-1-benzothien-2-yl) carbonyl] -4-phenylpiperidine with hydrogen gas and Pd / C -5-amine was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.64 (d, J = 8.6 Hz, 1H), 7.48 (s, 1H), 7.35 (m, 5H), 7.02 (s, 1H), 6.84 (d, J = 8.6 Hz, 1H), 5.21 (brs, 2H) 3.18 (m, 2H), 2.91 (m, 3H), 1.90 (m, 4H); ES-LCMS m / z 337 (M + H).

Step C: 2-[(4-Phenylpiperidin-1-yl) methyl] -1-benzothiophen-5-amine Using an experimental procedure similar to that in Example 106, Step E, 2-[(4- Phenylpiperidin-1-yl) carbonyl] -1-benzothiophen-5-amine is reduced with LAH to give 2-[(4-phenylpiperidin-1-yl) methyl] -1-benzothiophen-5-amine Was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.51 (d, J = 8.5 Hz, 1H), 7.34 (m, 5H), 7.05 (s, 1H), 6.90 (s, 1H), 6.69 (d, J = 8.6 Hz, 1H), 5.03 (brs, 2H), 3.75 (s, 2H), 3.18 (m, 5H), 1.90 (m) , 4H); ES-LCMS m / z 323 (M + H).

Step D: 6- (4-Chlorophenyl) -3- {2-[(4-phenylpiperidin-1-yl) methyl] -1-benzothien-5-yl} thieno [3,2-d] pyrimidine-4 ( 3H) -one Using an experimental procedure similar to that in Example 2, Step D, 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thiophene-2-carboxyl The title compound was prepared by reacting the rate (Example 1, Step D) with 2-[(4-phenylpiperidin-1-yl) methyl] -1-benzothiophen-5-amine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.53 (s, 1H), 8.14 (d, J = 8.6 Hz, 1H), 8.04 (s, 1H), 7.9 (m, 3H), 7.64 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.35 (m, 6H) 3.90 (s, 2H), 3.09 (m, 5H), 1.91 (m, 4H); ES-LCMS m / z 568 (M + H).

6- (4-Chlorophenyl) -3- {2-[(4-phenylpiperazin-1-yl) methyl] -1-benzothien-5-yl} thieno [3,2-d] pyrimidine-4 (3H)- on

Step A: 1-[(5-Nitro-1-benzothien-2-yl) carbonyl] -4-phenylpiperazine Using a similar experimental procedure as in Example 106, Step C, 5-nitro-1-benzo 1-[(5-Nitro-1-benzothien-2-yl) carbonyl] -4-phenylpiperazine was prepared by reacting thiophene-2-carboxylic acid with 1-phenylpiperazine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.91 (s, 1H), 8.31 (d, J = 9.0 Hz, 1H), 8.30 (d, J = 9.0 Hz, 1H), 8.08 (s, 1H), 7.28 (m, 2H), 7.02 (m, 2H), 6.97 (m, 1H), 3.28 (m, 4H), 2.55 (m , 4H); ES-LCMS m / z 368 (M + H).

Step B: 2-[(4-Phenylpiperazin-1-yl) carbonyl] -1-benzothiophen-5-amine Using the same experimental procedure as in Example 106, Step D, 1-[(5- Nitro-1-benzothien-2-yl) carbonyl] -4-phenylpiperazine is reduced with hydrogen gas and Pd / C to give 2-[(4-phenylpiperazin-1-yl) carbonyl] -1-benzothiophene -5-amine was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.65 (d, J = 8.7 Hz, 1H), 7.52 (s, 1H), 7.30 (m, 2H), 7.03 (m, 3H), 6.86 (m, 2H), 5.25 (brs, 2H), 3.24 (m, 4H), 2.56 (m, 4H); ES-LCMS m / z 338 (M + H).

Step C: 2-[(4-Phenylpiperazin-1-yl) methyl] -1-benzothiophen-5-amine Using an experimental procedure similar to that in Example 106, Step E, 2-[(4- Phenylpiperazin-1-yl) carbonyl] -1-benzothiophen-5-amine is reduced with LAH to give 2-[(4-phenylpiperazin-1-yl) methyl] -1-benzothiophen-5-amine. Was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.53 (d, J = 8.6 Hz, 1H), 7.20 (m, 2H), 7.02 (s, 1H), 7.0-6. 65 (m, 5H), 5.04 (brs, 2H), 3.78 (s, 2H), 3.24 (m, 4H), 2.54 (m, 4H); ES-LCMS m / z 323 (M + H).

Step D: 6- (4-Chlorophenyl) -3- {2-[(4-phenylpiperazin-1-yl) methyl] -1-benzothien-5-yl} thieno [3,2-d] pyrimidine-4 ( 3H) -one Using an experimental procedure similar to that in Example 2, Step D, 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thiophene-2-carboxyl. The title compound was prepared by reacting the rate (Example 1, Step D) with 2-[(4-phenylpiperazin-1-yl) methyl] -1-benzothiophen-5-amine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.54 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.9 (m, 6H), 7.64 (d, J = 8.5 Hz, 1H), 7.51 (m, 1H), 7.39 (s, 1H), 7.27 (m, 1H), 6.98-6 .81 (m, 2H), 3.93 (s, 2H), 3.24 (m, 4H), 2.54 (m, 4H); ES-LCMS m / z 569 (M + H).

6- (4-Chlorophenyl) -3- {2-[(dimethylamino) methyl] -1-benzothien-5-yl} thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: N, N-Dimethyl-5-nitro-1-benzothiophene-2-carboxamide Using an experimental procedure similar to that in Example 106, Step C, 5-nitro-1-benzothiophene-2-carboxylic acid N, N-dimethyl-5-nitro-1-benzothiophene-2-carboxamide was prepared by reacting an acid with N, N-dimethylamine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.90 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.29 (d, J = 9.0 Hz, 1H), 8.10 (s, 1H), 3.29 (s, 3H), 3.10 (s, 3H); ES-LCMS m / z 251 (M + H).

Step B: 5-Amino-N, N-dimethyl-1-benzothiophene-2-carboxamide Using the same experimental procedure as in Example 106, Step D, N, N-dimethyl-5-nitro-1- 5-amino-N, N-dimethyl-1-benzothiophene-2-carboxamide was prepared by reducing benzothiophene-2-carboxamide with hydrogen gas and Pd / C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.63 (d, J = 8.7 Hz, 1H), 7.53 (s, 1H), 7.01 (s, 1H), 6.84 (d, J = 8.6 Hz, 1H), 5.21 (brs, 2H), 3.21 (s, 6H); ES-LCMS m / z 221 (M + H).

Step C: 2-[(Dimethylamino) methyl] -1-benzothiophen-5-amine Using the same experimental procedure as in Example 106, Step E, 5-amino-N, N-dimethyl-1- 2-[(Dimethylamino) methyl] -1-benzothiophen-5-amine was prepared by reducing benzothiophene-2-carboxamide with LAH. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.53 (d, J = 8.6 Hz, 1H), 7.48 (s, 1H), 7.02 (s, 1H), 6.89 (d, J = 8.6 Hz, 1H), 5.03 (brs, 2H), 3.63 (s, 2H), 2.21 (s, 6H); ES-LCMS m / z 207 (M + H).

Step D: 6- (4-Chlorophenyl) -3- {2-[(dimethylamino) methyl] -1-benzothien-5-yl} thieno [3,2-d] pyrimidin-4 (3H) -one 2, Using the same experimental procedure as in Step D, 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thiophene-2-carboxylate (Example 1, The title compound was prepared by reacting Step D) with 2-[(dimethylamino) methyl] -1-benzothiophen-5-amine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 8.28 (d, J = 8.6 Hz, 1H), 8.19 (s, 1H), 8.05 (m, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.83 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H) 3.57 (s, 2H), 2.82 (s, 6H); ES-LCMS m / z 452 (M + H).

6- (4-Chlorophenyl) -3- {2-[(4-methylpiperazin-1-yl) methyl] -1-benzothien-5-yl} thieno [3,2-d] pyrimidine-4 (3H)- on

Step A: 1-Methyl-4-[(5-nitro-1-benzothien-2-yl) carbonyl] piperazine Using the same experimental procedure as in Example 106, Step C, 5-nitro-1-benzo 1-methyl-4-[(5-nitro-1-benzothien-2-yl) carbonyl] piperazine was prepared by reacting thiophene-2-carboxylic acid with N-methylpiperazine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.90 (s, 1H), 8.37 (d, J = 9.0 Hz, 1H), 8.17 (d, J = 8.9 Hz, 1H), 8.01 (s, 1H), 3.72 (m, 4H), 2.47 (m, 4H), 2.25 (s, 3H); ES-LCMS m / z 306 (M + H).

Step B: 2-[(4-Methylpiperazin-1-yl) carbonyl] -1-benzothiophen-5-amine Using the same experimental procedure as in Example 106, Step D, 1-methyl-4- By reducing [(5-nitro-1-benzothien-2-yl) carbonyl] piperazine with hydrogen gas and Pd / C, 2-[(4-methylpiperazin-1-yl) carbonyl] -1-benzothiophene -5-amine was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.63 (d, J = 8.5 Hz, 1 H), 7.44 (s, 1 H), 7.01 (s, 1 H), 6.84 (d, J = 8.5 Hz, 1H), 5.23 (brs, 2H), 3.69 (t, J = 4.7 Hz, 4H), 2.41 (t, J = 4.8 Hz, 4H), 2. 12 (s, 3H); ES-LCMS m / z 276 (M + H).

Step C: 2-[(4-Methylpiperazin-1-yl) methyl] -1-benzothiophen-5-amine Using an experimental procedure similar to that in Example 106, Step E, 2-[(4- Reduction of methylpiperazin-1-yl) carbonyl] -1-benzothiophen-5-amine with LAH yields 2-[(4-methylpiperazin-1-yl) methyl] -1-benzothiophen-5-amine Was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.51 (d, J = 8.7 Hz, 1H), 7.46 (s, 1H), 7.02 (s, 1H), 6.86 (d, J = 8.7 Hz, 1H), 5.0 (brs, 2H), 3.78 (s, 2H), 2.42 (m, 4H), 2.40 (m, 4H), 2.14 (s , 3H); ES-LCMS m / z 262 (M + H).

Step D: 6- (4-Chlorophenyl) -3- {2-[(4-methylpiperazin-1-yl) methyl] -1-benzothien-5-yl} thieno [3,2-d] pyrimidine-4 ( 3H) -one Using an experimental procedure similar to that in Example 2, Step D, 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thiophene-2-carboxyl. The title compound was prepared by reacting the rate (Example 1, Step D) with 2-[(4-methylpiperazin-1-yl) methyl] -1-benzothiophen-5-amine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.48 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.93 (m, 3H), 7.58 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.6, Hz, 1H), 7.36 (s, 1H), 3.79 (s, 2H), 2.41-2.22 (m, 8H), 2.14 (s, 3H); ES-LCMS m / z 507 (M + H).

6- (4-Chlorophenyl) -3- (2-{[(3R) -3-hydroxypyrrolidin-1-yl] methyl} -1-benzothien-5-yl) thieno [3,2-d] pyrimidine-4 (3H) -ON

Step A: (3R) -1-[(5-Nitro-1-benzothien-2-yl) carbonyl] pyrrolidin-3-ol Using the same experimental procedure as in Example 106, Step C, By reacting -1-benzothiophene-2-carboxylic acid with (3R) -pyrrolidin-3-ol, (3R) -1-[(5-nitro-1-benzothien-2-yl) carbonyl] pyrrolidine -3-ol was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.90 (s, 1H), 8.36 (d, J = 9.0 Hz, 1H), 8.10 (d, J = 8.9 Hz, 1H), 8.01 (s, 1H), 4.23 (m, 1H), 3.94 (brs, 1H), 3.61-3.33 (m, 4H), 1.89 (m, 2H); ES -LCMS m / z 293 (M + H).

Step B: (3R) -1-[(5-Amino-1-benzothien-2-yl) carbonyl] pyrrolidin-3-ol Using the same experimental procedure as in Example 106, Step D, (3R) Reduction of -1-[(5-nitro-1-benzothien-2-yl) carbonyl] pyrrolidin-3-ol with hydrogen gas and Pd / C gives (3R) -1-[(5-amino-1 -Benzothien-2-yl) carbonyl] pyrrolidin-3-ol was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.51 (d, J = 8.6 Hz, 1H), 7.41 (s, 1H), 7.01 (s, 1H), 6.82 (d, J = 8.7 Hz, 1H), 5.23 (brs, 2H), 4.21 (m, 1H), 3.96 (brs, 1H), 3.63 to 3.31 (m, 4H), 1 .90 (m, 2H); ES-LCMS 263 m / z (M + H).

Step C: (3R) -1-[(5-Amino-1-benzothien-2-yl) carbonyl] pyrrolidin-3-ol Using the same experimental procedure as in Example 106, Step E, 2- [ (3R) -1-[(5-amino-1-benzothien-2-yl) carbonyl is obtained by reducing (4-methylpiperazin-1-yl) carbonyl] -1-benzothiophen-5-amine with LAH. Pyrrolidin-3-ol was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.43 (d, J = 8.4 Hz, 1H), 6.94 (s, 1H), 6.82 (s, 1H), 6.61 (d, J = 8.4 Hz, 1H), 5.01 (brs, 2H), 4.61 (brs, 1H), 4.23 (m, 1H), 3.77 (s, 2H), 2.65 (m) , 2H), 2.31 (m, 2H), 1.98 (m, 1H), 1.45 (m, 1H); ES-LCMS m / z 249 (M + H).

Step D: 6- (4-Chlorophenyl) -3- (2-{[(3R) -3-hydroxypyrrolidin-1-yl] methyl} -1-benzothien-5-yl) thieno [3,2-d] Pyrimidin-4 (3H) -one Using the same experimental procedure as in Example 2, Step D, 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino) methylidene] amino} thiophene By reacting 2-carboxylate (Example 1, Step D) with (3R) -1-[(5-amino-1-benzothien-2-yl) carbonyl] pyrrolidin-3-ol, the title The compound was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.49 (s, 1 H), 8.07 (d, J = 8.6 Hz, 1 H), 7.99 (s, 1 H), 7.93 (m, 3H), 7.58 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.6 Hz, 1H), 7.35 (s, 1H), 4.73 (brs, 1H) 4.21 (m, 1H), 3.90 (s, 2H), 2.81 to 48 (m, 3H), 2.41 (m, 1H), 1.98 (m, 1H), 1. 48 (m, 1 H); ES-LCMS m / z 494 (M + H).

6- (4-Chlorophenyl) -3- [6- (pyrrolidin-1-ylmethyl) -2-naphthyl] thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: 6- (Pyrrolidin-1-ylcarbonyl) naphthalen-2-amine To a DMF solution (100 mL) containing 6-amino-2-naphthoic acid (5 g, 26.71 mmol, 1.0 equiv), N, N-diisopropylethylamine (5.58 mL: 32.05 mmol, 1.2 eq) was added followed by HATU (15.2 g, 40.07 mmol, 1.5 eq). The resulting solution was stirred at room temperature for 20 minutes. To this stirred solution was added pyrrolidine (2.7 mL, 32.05 mmol, 1.2 eq). The resulting solution was stirred at room temperature for 18 hours and quenched with saturated NaHCO ₃ solution (ca. 20 mL). The cloudy solution was then poured into H ₂ O (ca. 100 mL) and extracted with EtOAc (3 × 25 mL). The combined organic extracts were washed with H ₂ O (2 ×) and brine (1 ×), dried over MgSO ₄ and concentrated in vacuo. The resulting off-white solid (4.57 g, 19.02 mmol, 71%) was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.61 (m, 2H), 6.92 (s, 2H) 3.93 (bs, 2H), 3.71 (m, 2H), 3.56 (m, 2H), 2.03 (m, 4H).

Step B: 6- (Pyrrolidin-1-methyl) naphthalen-2-amine A solution of Example 113, Step A (4.57 g, 19.02 mmol, 1.0 eq) in anhydrous THF (100 mL) was added to lithium aluminum hydride. (1.8 g, 47.55 mmol, 2.5 eq) in cold (0 ° C.) anhydrous THF (200 mL) suspension. The resulting mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction was quenched by sequential addition of H ₂ O (1.8 mL), 15% NaOH (1.8 mL) and H ₂ O (5.4 mL). The resulting precipitate was filtered and washed with THF. The filtrate was concentrated in vacuo and the resulting solid (4.3 g, 19.02 mmol, 100%) was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (m, 3H), 7.39 (dd, J = 8.4, 1.6 Hz, 1H), 6.98 (d, J = 2.1 Hz, 1H) ), 6.95 (dd, J = 8.6, 2.2 Hz, 1H), 3.83 (bs, 2H), 3.73 (s, 2H), 2.59 (m, 4H), 1. 82 (m, 4H).

Step C: 6- (4-Chlorophenyl) -3- [6- (pyrrolidin-1-ylmethyl) -2-naphthyl] thieno [3,2-d] pyrimidin-4 (3H) -one Example 113, Step B Intermediate compound (11.8 g, 52.21 mmol, 1.3 eq) and 5- (4-chlorophenyl) -3-{[(E)-(dimethylamino) methylidene] amino} -2-thiophene To a dichloroethane solution (80 mL) containing methyl carboxylate (12.93 g, 40.16 mmol, 1.0 equivalent, as above), AlMe ₃ in hexane (60.24 mL, 120.48 mmol, 3.0 equivalent) Was added dropwise. The resulting mixture is heated to reflux for 3 hours, then cooled to room temperature and placed in an ice bath. Formic acid (200 mL) was added very slowly and the resulting mixture was heated to reflux for 4 hours. After cooling to room temperature, the aqueous phase was made basic by adding 50% NaOH solution. The organic phase was separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 ×). The combined organic extracts were dried over MgSO ₄ and concentrated in vacuo. The resulting solid was triturated with a small amount of CH ₂ Cl ₂ to purify the title compound (13.4 g, 28.38 mmol, 70%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.85 (m, 3H), 7.68 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.6 Hz, 1H), 7.55 (s, 1H), 7.53 (dd, J = 8.6, 1.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 3.81 (s, 2H), 2.56 (m, 4H), 1.82 (m, 4H). AP-LCMS m / z 473 (M + H).

6- (4-Chlorophenyl) -3- {6-[(dimethylamino) methyl] -2-naphthalenyl} thieno [3,2-d] pyrimidin-4 (3H) -one A solution of AlMe ₃ in hexane (0.38 mL) , 0.75 mmol) to [(6-amino-2-naphthalenyl) methyl] dimethylamine (0.10 g, 0.50 mmol) and 5- (4-chlorophenyl) -3-{[(1E)-(dimethylamino ) methylidene] amino} -2-thiophenecarboxylate (example 1, was added slowly at room temperature, _{N 2} below into dichloroethane (5 mL) solution of step D, 0.16 g, 0.50 mmol). After 5 minutes, the solution was heated to reflux for 2 hours and then cooled to room temperature. Formic acid (3 mL) was added carefully and the mixture was heated to reflux for 6 hours. Upon cooling to room temperature, 1N aqueous NaOH was added until the pH of the aqueous phase was alkaline, followed by CH ₂ Cl ₂ (250 mL) and water (100 mL). The organic layer was separated, dried over MgSO ₄ , filtered and concentrated to give the title compound as a white solid (0.20 g) with a purity of about 80%. The solid was partially dissolved in warm CHCl ₃ , filtered and concentrated. The resulting solid was dissolved in CHCl ₃ (15 mL) and then Et ₂ O (25 mL) was added, which produced a white precipitate. The solid was filtered and dried in vacuo to give the title compound as a white powder (0.089 g, 40%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.89-7.84 (m, 3H), 7.68 ( d, J = 8.4 Hz, 2H), 7.61 to 7.52 (m, 3H), 7.45 (d, J = 8.5 Hz, 2H), 3.64 (s, 2H), 2. 32 (s, 6H). EI-LCMS m / z 446 (M + H).

6- (4-Chlorophenyl) -3- [6- (1-pyrrolidinylmethyl) -2-naphthalenyl] thieno [3,2-d] pyrimidin-4 (3H) -one maleate AlMe ₃ in hexane (5.36 mL, 10.71 mmol) was converted to [6- (1-pyrrolidinylmethyl) -2-naphthalenyl] amine (1.05 g, 4.65 mmol) and 5- (4-chlorophenyl) -3-{[( 1E)-(Dimethylamino) methylidene] amino} -2-thiophenecarboxylate (Example 1, Step D, 1.15 g, 3.57 mmol) in dichloroethane (40 mL) slowly at room temperature under N ₂ added. After 5 minutes, the solution was heated to reflux for 3 hours and then cooled to room temperature. Formic acid (25 mL) was carefully added and the mixture was heated to reflux for 4 hours. Once cooled to room temperature, 1N aqueous NaOH was added until the pH of the aqueous phase was alkaline. Extracted with CH ₂ Cl ₂ (2 × 250 mL) and the organic phase was separated, dried over MgSO ₄ , filtered and concentrated. The solid was purified by column chromatography on silica gel eluting with an ascending gradient from ethyl acetate to 10% MeOH / ethyl acetate to give the title compound in about 75% purity. The solid was dissolved in warm DMSO, cooled to room temperature and filtered. The resulting solid (1.1 g) was partially dissolved in CHCl ₃ and maleic acid (1 equivalent) was added. The solution was filtered and concentrated to give the title compound as the maleate salt (0.89 g, 45%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.90 (br s, 1H), 8.58 (s, 1H), 8.22 to 8.11 (m, 4H), 8.04 (s, 1H), 7.96 (d, J = 8.6 Hz, 2H), 7.78 to 7.73 (m, 2H), 7.60 (d, J = 8.6 Hz, 2H), 6.03 (s, 2H) ), 4.56 (s, 4H), 3.35 to 3.10 (m, 4H), 2.11 to 1.84 (m, 4H). EI-LCMS m / z 472 (M + H).

6- (4-Chlorophenyl) -3- {1- [2- (1-pyrrolidinyl) ethyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: (2,4-Dinitrophenyl) [2- (1-pyrrolidinyl) ethyl] amine 2,4-dinitrofluorobenzene (18.6 g, 0.10 mmol) was added to [2- (1-pyrrolidinyl) ethyl]. To a stirred THF (150 mL) solution consisting of amine (11.40 g, 0.10 mmol) and triethylamine (10.19 g, 0.10 mol). After stirring for 2 hours at ambient temperature, the reaction is diluted with sodium hydroxide (20 mL, 5N), diluted with ethyl acetate, extracted twice with brine, once with water, dried, filtered and concentrated. A yellow powder (28.0 g, 100%) was obtained. LCMS m / z 281 (MH +). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.00 (m, 1H), 8.80 (s, 1H), 8.22 (d, 1H), 7.20 (d, 1H), 3.56 (M, 2H), 2.77 (t, 2H), 2.55 (m, 4H), 1.70 (m, 4H).

Step B: (2,4-Dinitrophenyl) [2- (1- (2- (1-pyrrolidinyl) ethyl] -1H-benzimidazol-5-amine Pd (OH) _{2 /} C (2.0 g)) A solution of 1-pyrrolidinyl) ethyl] amine (28.0 g, 0.10 mmol) in dioxane (200 mL) was stirred on a Parr shaker for 3 hours under 45 psi hydrogen pressure. The reaction mixture was released into a nitrogen atmosphere, filtered through celite and mixed with triethyl orthoformate (100 mL) and HCl / dioxane (20 mL, 4M). After heating to reflux overnight, the reaction is concentrated, mixed with aqueous sodium hydroxide (20 mL, 5N), extracted with ethyl acetate, concentrated and chromatographed on silica gel using EtOH: EtOAc / 1: 1. Upon processing, a deep tan solid (20 g, 87%) was obtained. LCMS m / z 231 (MH +). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.24 (s, 1H), 8.20 (s, 1H), 8.00 (d, 1H), 7.51 (d, 1H), 4.70 (M, 2H), 4.35 (t, 2H), 2.77 (t, 2H), 2.55 (m, 4H), 1.64 (m, 4H).

Step C: 6- (4-Chlorophenyl) -3- {1- [2- (1-pyrrolidinyl) ethyl] -1H-benzimidazol-5-yl} thieno [3,2-d] pyrimidine-4 (3H) -ON 1- [2- (1-pyrrolidinyl) ethyl] -1H-benzimidazol-5-amine (0.46 g, 0.002M) and 5- (4-chlorophenyl) -3-{[(1E)-( A solution of methyl (dimethylamino) methylidene] amino} -2-thiophenecarboxylate (Example 1, Step D, 0.319 g, 0.001 mol) in ethanol (10 mL) is heated to reflux overnight and then filtered at ambient temperature. A tan solid (0.155 g, 32%) was then obtained. LCMS m / z 476 (MH +). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.50 (s, 1H), 8.40 (s, 1H), 8.03 (s, 1H), 7.97 (d, 2H), 7.84 (S, 1H), 7.80 (d, 1H), 7.62 (d, 2H), 7.40 (d, 1H), 4.44 (t, 2H), 2.84 (t, 2H) 2.42-2.58 (m, 4H), 1.64 (m, 4H).

6- (4-Chlorophenyl) -3- (2-{[2- (1-pyrrolidinyl) ethyl] amino} -1H-benzimidazol-5-yl) thieno [3,2-d] pyrimidine-4 (3H) -ON

Step A: 5-Nitro-N- [2- (1-pyrrolidinyl) ethyl] -1H-benzimidazol-2-amine 2-chloro-5-nitro-1H-benzimidazole (1.0 g, 5.06 mmol) A 20 mL solution of ethanol was treated with [2- (1-pyrrolidinyl) ethyl] amine (835 μL, 6.6 mmol) and heated to reflux for 1 hour. Further [2- (1-pyrrolidinyl) ethyl] amine (1670 μL, 13.2 mmol) was added and placed in a sealed tube at 160 ° C. overnight. Concentration of the reaction solution produced an oil, which was 5-nitro-N- [2- (1-pyrrolidinyl) ethyl] -1H-benzimidazol-2-amine and [2- (1-pyrrolidinyl) ethyl. It was a mixture with amine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.7 (m, 4H) 2.4 (m, 4H) 2.5 (m, 2H) 2.6 (t, J = 6.6 Hz, 2H) 7 .2 (d, J = 8.8 Hz, 1H) 7.9 (dd, J = 8.8, 2.4 Hz, 1H) 7.9 (d, J = 2.4 Hz, 1H). ES-LCMS m / z 276 (M + H).

Step ^B: N 2 - [2- (1-pyrrolidinyl) ethyl]-1H-5-nitro -N- obtained in benzimidazole-2,5-diamine preceding reaction [2- (1-pyrrolidinyl) ethyl] A mixture of -1H-benzimidazol-2-amine and [2- (1-pyrrolidinyl) ethyl] amine is dissolved in 30 mL of ethanol and treated with 10% palladium on carbon (500 mg, 0.46 mmol); Hydrogenated at 30 psi with Parr apparatus. When hydrogen uptake was complete, the reaction was filtered through a silica / celite plug and concentrated in vacuo. Chromatography on silica 12g using 2M ammonia / dichloromethane 0-10% ^methanol, N 2 - [2- (1-pyrrolidinyl) ethyl]-1H-benzimidazole-2,5-diamine [2- ( 1-pyrrolidinyl) ethyl] amine (800 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.7 (m, 4H) 2.4 (m, 2H) 2.5 (t, J = 6.4 Hz, 2H) 2.6 (t, J = 6 .6 Hz, 2H) 2.8 (t, J = 6.2 Hz, 2H) 6.2 (dd, J = 8.1, 2.0 Hz, 1H) 6.4 (d, J = 1.8 Hz, 1H) 6.8 (d, J = 8.2 Hz, 1H)

Step C: 6- (4-Chlorophenyl) -3- (2-{[2- (1-pyrrolidinyl) ethyl] amino} -1H-benzimidazol-5-yl) thieno [3,2-d] pyrimidine-4 (3H) - on the preceding reaction resulting ^N 2 - [2- (1-pyrrolidinyl) ethyl]-1H-benzimidazole-2,5-diamine and [2- (1-pyrrolidinyl) ethyl] with an amine The mixture was treated with methyl 5- (4-chlorophenyl) -3-{[(E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate (1.05 g, 3.26 mmol) in 5 g of phenol. And heated at 170 ° C. for 2 hours. The reaction was directly chromatographed on 40 g silica using 0-10% 2M ammonia in methanol / dichloromethane to give the desired product (449 mg). The by-product 6- (4-chlorophenyl) -3- [2- (1-pyrrolidinyl) ethyl] thieno [3,2-d] pyrimidin-4 (3H) -one (139 mg) was also isolated. ¹ H NMR (400 MHz DMSO-d ₆ ) δ 1.7 (m, 4H) 2.5 (m, 4H) 2.6 (t, J = 6.6, 6.2 Hz, 2H) 3.4 (m, 2H) 6.7 (t, J = 5.9 Hz, 1H) 6.9 (dd, J = 8.2, 2.0 Hz, 1H) 7.2 (d, J = 8.2 Hz, 1H) 2 (d, J = 2.2 Hz, 1H) 7.6 (d, J = 8.8 Hz, 2H) 7.9 (d, J = 8.8 Hz, 2H) 8.0 (m, 1H) 4 (m, 1H). ES-LCMS m / z 491 (M + H).

6- (4-Chlorophenyl) -3- (2,3-dihydro-1H-imidazo [1,2-a] benzimidazol-7-yl) thieno [3,2-d] pyrimidin-4 (3H) -one

Step A: (2-{[[(2-Bromo-5-nitrophenyl) amino] (dimethylamino) methylidene] amino} ethyl) 1,1-dimethylethyl carbamate N '-(2-bromo-5-nitro Phenyl) -N, N-dimethylcarbamine imido chloride (1.64 mmol) in dichloromethane (20 mL) was added to triethylamine (1.14 mL, 8.2 mmol) and (2-aminoethyl) carbamate 1,1-dimethylethyl (395 mg). 2.46 mmol) and stirred for 36 hours. There was no reaction. Dichloromethane was distilled off and replaced with 10 mL of tetrahydrofuran, and the reaction solution was heated to reflux overnight. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.3 (s, 9H) 2.7 (s, 6H) 2.9 (m, 2H) 3.6 (m, 1H) 7.3 (m, 2H 7.7 (d, J = 9.0 Hz, 1H).

Step B: {1- [2- (Dimethylamino) -5-nitro-1H-benzimidazol-1-yl] ethyl} 1,1-dimethylethyl carbamate (2-{[[(2-Bromo-5- Tetrahydrofuran consisting of 1,1-dimethylethyl (1.64 mmol), BINAP (92 mg, 0.15 mmol) and cesium carbonate (746 mg, 2.3 mmol) nitrophenyl) amino] (dimethylamino) methylidene] amino} ethyl) carbamate The 16 mL solution was treated with palladium acetate (22 mg, 0.1 mmol) and heated to reflux for 24 hours. Additional BINAP and palladium acetate were added and the reaction was refluxed for an additional 24 hours. The reaction was diluted with 1N sodium hydroxide and extracted with dichloromethane. The organics were dried over magnesium sulfate, concentrated in vacuo, and the residue was chromatographed on 12 g silica with 0-10% methanol / dichloromethane to give the desired product, which was obtained with BINAP. It was contaminated. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.4 (s, 9H) 3.0 (s, 6H) 3.4 (dt, J = 6.2 Hz, 2H) 4.2 (t, J = 6.4 Hz) , 2H) 5.0 (t, J = 5.7 Hz, 1H) 7.2 (d, J = 8.8 Hz, 1H) 8.0 (dd, J = 8.8, 2.0 Hz, 1H) 8 .3 (d, J = 2.0 Hz, 1H).

Step C: {1- [5-Amino-2- (dimethylamino) -1H-benzimidazol-1-yl] ethyl} 1,1-dimethylethyl carbamate {2- [2- (Dimethylamino) -5-nitro-1H-benzimidazol-1-yl] ethyl} carbamate 1,1-dimethylethyl and BINAP are dissolved in 20 mL of ethanol and 10% palladium on carbon (250 mg, 250 mg, 0.23 mmol) and hydrogenated on a Parr apparatus at 40 psi. When hydrogen uptake was complete, the reaction was filtered through a plug of silica / celite and concentrated in vacuo to produce the desired product, which was contaminated with BINAP. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.4 (s, 9H) 2.9 (s, 6H) 3.4 (dt, J = 7.0, 6.0, 5.3 Hz, 2H) 4.1 (T, J = 6.2 Hz, 2H) 4.9 (t, J = 4.9 Hz, 1H) 6.5 (dd, J = 8.2, 1.8 Hz, 1H) 6.9 (d, J = 1.6 Hz, 1H) 7.0 (d, J = 8.2 Hz, 1H).

Step D: 6- (4-Chlorophenyl) -3- (2,3-dihydro-1H-imidazo [1,2-a] benzimidazol-7-yl) thieno [3,2-d] pyrimidine-4 (3H ) -One A mixture of 1,2-dimethylethyl {2- [5-amino-2- (dimethylamino) -1H-benzimidazol-1-yl] ethyl} carbamate obtained in the previous reaction and BINAP. , 5- (4-chlorophenyl) -3-{[(E)-(dimethylamino) methylidene] amino} -2-thiophenecarboxylate (270 mg, 0.84 mmol), in 1 g of phenol at 200 ° C. Heated for 1 hour. Once cooled, the reaction was diluted with methanol and the resulting precipitate was collected by filtration. The residue was dissolved in dimethyl sulfoxide, treated with 4N HCl in dioxane and precipitated by adding ethyl acetate and diethyl ether to give 6- (4-chlorophenyl) -3- (2,3-dihydro-1H- 139 mg of imidazo [1,2-a] benzimidazol-7-yl) thieno [3,2-d] pyrimidin-4 (3H) -one was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.5 (s, 1H) 4.3 (m, 4H) 7.4 (dd, J = 8.4, 1.8 Hz, 1H) 7.6 (m , 3H) 7.6 (d, J = 1.8 Hz, 1H) 7.9 (d, J = 8.6 Hz, 2H) 8.0 (s, 1H) 8.4 (s, 1H) 9.5 (Brs, 1H). ES-LCMS m / z 420 (M + H).

  The activity of the compounds used in the present invention can be assessed in a MCHR1 functional assay as follows.

Materials Black 96-well tissue culture treated plates (# 3904) were obtained from Corning Costar (Cambridge, MA) and LucPlus ™ Luciferase Reporter Gene Assay Kit (# 6016969) Packard CT (Merida). ) And a plate seal (# 097-05-00006) was obtained from Beckman / Sagian (Fullerton, Calif.). DMEM / F12 medium (# 11039-021), fetal bovine serum (# 16140-071), L-glutamine (# 25030-081), 0.05% trypsin (# 25300-054), G418 (# 10131-035) And dPBS (# 4190-144) were obtained from Gibco BRL (Gaithersburg, MD). Thrombin (T7009) was obtained from Sigma Chemical Co (St. Louis, MO) and MCH peptide (H-1482) was obtained from BaChem California (Torrance, CA). Chinese hamster ovary (CHO-K1) cells were obtained from the American Type Culture Collection (Rockville, MD).

Methods CHO cells (host) stably expressing elkgal4-luc ⁺ reporter gene were transfected with human melamine-concentrating hormone 1 receptor by electroporation. G418 was used to select stable clones for functional antagonist assays. MCH1R-elkgal4-luc ⁺ CHO cells were grown in complete medium (DMEM / F12, 5% FBS, 2 mM I-glutamine) in T225 flasks. Forty-eight hours prior to assay, cells were harvested with 2 mL of 0.05% trypsin, washed with complete medium, and placed in complete medium in black 96-well plates at a concentration of 10,000 cells / well. 18 hours before the assay, the medium was removed from the cells by aspiration and replaced with 90 μl of serum free DMEM / F12 per well. At the time of the assay, antagonist (1 μL, 100% DMSO) was pipetted into the medium as a 10 point concentration curve and the plates were incubated for 45 minutes at 37 ° C. in a cell culture incubator. After this incubation, 10 μL of EC ₈₀ concentration of MCH was added to the medium and the plates were incubated for 5 hours at 37 ° C. in a cell culture incubator. The medium was aspirated by vacuum, followed by, LucPlus (TM) and dPBS / 1 mM of CaCl _2/1 mM of MgCl ₂ of 1: plus 1 mixture 50 [mu] l. An aspiration step was performed to avoid assay interference that could be caused by compounds that could inhibit or stimulate luciferase activity or inhibit light signals. Plates were sealed and dark adapted for 10 minutes at room temperature, after which luciferase activity was quantified on a TopCount ™ microplate scintillation counter (Packard) using a count time of 3 seconds / well. A curve fitting program based on MicrosoftExCel was used to quantify the ability of the antagonist to inhibit the MCH EC ₈₀ response by non-linear regression analysis. Using the same protocol, the specificity of the MCHR1 response was determined by measuring the ability of the antagonist to inhibit the EC ₈₀ thrombin response (endogenous) in host cells.

The compounds described in the examples have a pIC ₅₀ value greater than 7. For example, the compounds of Examples 1 and 11 have MCHR1 pIC ₅₀ as shown below respectively. Also included are exemplified compounds from Takeda's WO 01/82925 A1 pamphlet. As can be seen from Table 2, the compounds claimed herein have 10 times more activity than the examples cited from WO 01/82925 A1.

Claims (50)

A compound of formula (I), a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

[Where:

Is at least selected from the group consisting of C ₁ -C ₆ linear or branched alkyl, alkenyl, halo, amino, alkylamino, dialkylamino, hydroxy, C ₁ -C ₆ alkoxy, cyano, nitro and alkylthio groups An aryl or heteroaryl optionally substituted with 1 to 4 substituents,
The dotted line connecting Q ² and Q ³ represents an optional bond,
q, r, s and t are each independently 0 or 1,
when q is 1, the dotted line is a bond;
Q ¹ and Q ³ are each independently C or N;
when q is 0, Q ² is N, S or O;
when q is 1, Q ² is C or N; when q is 1 and Q ² is N, s is 0;
When Q ² is S or O, s is 0;
When Q ¹ is N, r is 0;
When Q ³ is N, t is 0;
R ³ is selected from the group consisting of hydrogen, amino, C ₁ -C ₆ linear or branched alkyl, C ₃ -C ₆ cycloalkyl and C ₁ -C ₃ alkylthio;
When Q ¹ or Q ³ is C, each corresponding R ⁴ is independently hydrogen, C ₁ -C ₆ linear or branched alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, Selected from the group consisting of amino, alkylamino, dialkylamino, hydroxy, cyano, alkylthio and halo;
When q is 1 and Q ² is C or q is 0 and Q ² is N, R ⁵ is hydrogen, C ₁ -C ₆ straight or branched alkyl, C _3- Selected from the group consisting of C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, alkylthio and halo;
Ar is an optionally substituted fused bicyclic ring,
Y is a bond or an optionally substituted C ₁ -C ₆ alkylene;
(I) R ¹ and R ² are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ straight or branched chain alkyl, C ₃ -C ₆ cycloalkyl and a 5 or 6 membered heterocycle. , The alkyl, the cycloalkyl and the heterocycle are substituted with 1 to 4 substituents selected from the group consisting of phenyl, C ₁ -C ₃ alkyl, hydroxy, oxo, alkoxy and halo. Or (ii) each of R ¹ and R ² is a group consisting of aryl and 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S is selected from the aryl and the heteroaryl, _halo, C 1 -C ₆ straight or branched chain _alkyl, C 3 -C _{6 cycloalkyl,} C 1 -C _Alkenyl, C 3 -C ₆ cycloalkenyl, _hydroxy, C 1 -C ₆ alkoxy, oxo, _amino, C 1 -C _{6 alkylamino,} C 1 -C _{6 dialkylamino,} C 1 -C _{6 alkylthio,} C 1 -C Optionally substituted with at least one substituent selected from the group consisting of ₆ alkylsulfinyl and phenyl, or (iii) R ¹ and R ² are the nitrogen to which they are attached. Together with the atoms, it forms a 4-8 membered heterocyclic ring or a 7-11 membered bicyclic heterocyclic ring, wherein the 4-8 membered heterocyclic ring and the 7-11 membered bicyclic heterocyclic ring are N, O and wherein 1, 2 or 3 heteroatoms selected from the group consisting of S, said any of a heterocyclic ring or the bicyclic heterocycle, phenyl, C ₁ -C ₃ alkyl, hydroxy, C -C ₃ alkoxy, oxo, _amino, C 1 -C _{6 alkylamino,} optionally substituted by at least one substituent one selected from the group consisting of C 1 -C ₆ dialkylamino, or halo 4 Or (iv) R ² may form an optionally substituted nitrogen-containing heterocycle with the adjacent nitrogen atom and Y, or R ² may be substituted with the adjacent nitrogen atom, Y and Ar may be formed by also be a nitrogen-containing optionally heterocyclic, or a salt thereof, wherein heterocycle, _phenyl, C 1 -C ₃ alkyl, _hydroxy, C 1 -C ₃ alkoxy, oxo, _amino, C 1 -C Optionally substituted with 1 to 4 at least one substituent selected from the group consisting of ₆ alkylamino, C ₁ -C ₆ dialkylamino and halo] Said

But halo, aryl substituted with at least one substituent selected from C ₁ -C ₃ alkyl and C ₁ -C ₃ group consisting of alkoxy, A compound according to claim 1.

3. The compound of claim 2, wherein is an aryl substituted with a group selected from the group consisting of fluoro, chloro and methoxy. Said

Is halo-substituted aryl or halo-substituted heteroaryl, q is 0, s is 0, Q ¹ is C, Q ² is S, R ⁴ is hydrogen or halo The compound of claim 1, wherein

There is a 4-chlorophenyl, ^{R 3} and ^{R 4} are each hydrogen, A compound according to claim 4. The compound of claim ¹ , wherein Q ¹ , Q ² and Q ³ are each C, and q, r, s and t are 1. The compound of claim 1, wherein Q ¹ is N, Q ² is S, and q, r, s, and t are 0. The compound of claim ₁ , wherein R ³ is hydrogen or C ₁ -C ₃ alkyl. R ³ is hydrogen or methyl, A compound according to claim 8.   2. The compound according to claim 1, wherein Ar is a 9-14 membered fused polycyclic aromatic ring or a 9-14 membered fused polycyclic heteroaromatic ring.   The compound according to claim 10, wherein the condensed polycyclic aromatic ring or the condensed polycyclic heteroaromatic ring is a 10-membered ring.   The compound according to claim 11, wherein the condensed polycyclic aromatic ring is naphthalene or the condensed polycyclic heteroaromatic ring is quinoline. Y is substituted it is also good C ₁ -C ₆ alkylene, A compound according to claim 11. Y is substituted it is also good C ₁ -C ₃ alkylene, A compound according to claim 13.   15. A compound according to claim 14, wherein Y is methylene. (I), the independently ^{R 1} and ^{R 2} are each selected from _hydrogen, C 1 -C ₆ straight or branched chain alkyl and _C 3 -C consisting ₆ alkyl group, as defined in claim 1 Compound. The compound according to claim 16, wherein in (i) R ¹ and R ² are independently selected from the group consisting of hydrogen, C ₁ -C ₃ linear or branched alkyl and C ₃ -C ₆ alkyl. . In (ii), one of R ¹ or R ² is aryl or heteroaryl, and the other of the remaining R ¹ or R ² is hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl The compound according to claim 1. In (iii) a 5- or 6-membered heterocycle in which R ¹ and R ² have 1 or 2 heteroatoms selected from the group consisting of N, O and S together with the nitrogen atom to which they are attached Alternatively, it forms an 8- to 11-membered bicyclic heterocycle, and the heterocycle and the bicyclic heterocycle may be substituted with 2 or less substituents selected from the group consisting of oxo and halo. The compound of claim 1. R ¹ and R ² together with the nitrogen atom to which they are attached, morpholine, piperidine, piperazine, pyrrolidine, 1,3-thiazolidine, 1H-imidazole, 4,5-dihydro-1H-imidazole, 2,3-dihydro indole, 1,2,3,4-tetrahydroquinoline and 1,2,3,4 consisting tetrahydroisoquinoline form a heterocyclic ring selected from the group, the heterocyclic ring, _phenyl, C 1 -C ₃ alkyl, 20. A compound according to claim 19 which is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxy, alkoxy, oxo and halo. In (iv), Y _is a C 1 -C ₆ alkylene, ^{R 2} is bonded to the Y, to form a 3 to 7-membered ring, A compound according to claim 1. The ring is optionally substituted with 1 to 4 at least one substituent selected from the group consisting of phenyl, C ₁ -C ₃ alkyl, hydroxy, alkoxy, oxo and halo. 24. The compound of claim 21, which is a ring. The compound is
6- (4-chlorophenyl) -3- {6-[(4-hydroxy-1-piperidinyl) methyl] -2-naphthalenyl} thieno [3,2-d] pyrimidin-4 (3H) -one,
6- (4-chlorophenyl) -3- [6- (pyrrolidin-1-ylmethyl) -2-naphthyl] thieno [3,2-d] pyrimidin-4 (3H) -one,
6- (4-Chlorophenyl) -3- {2-[(4-methylpiperazin-1-yl) methyl] -1-benzothien-5-yl} thieno [3,2-d] pyrimidine-4 (3H)- on,
6- (4-fluorophenyl) -3- [2- (pyrrolidin-1-ylmethyl) quinolin-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one,
6- (4-fluorophenyl) -3- [2- (piperidin-1-ylmethyl) quinolin-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one,
6- (4-Chlorophenyl) -3- {2-[(2-methyl-4,5-dihydro-1H-imidazol-1-yl) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidine -4 (3H) -on,
6- (4-Chlorophenyl) -3- {2-[(2,2,6,6-tetramethylpiperidin-1-yl) methyl] quinolin-6-yl} thieno [3,2-d] pyrimidine-4 Selected from the group consisting of (3H) -one and 6-phenyl-3- [2- (pyrrolidin-1-ylmethyl) quinolin-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one The compound of claim 1, wherein   11. The compound according to claim 10, wherein Ar is a 9-membered fused polycyclic heteroaromatic ring.   25. A compound according to claim 24, wherein Ar is benzimidazole, indole, benzothiophene, benzothiazole or benzofuran. Y is a bond or is a _C 1 -C ₃ alkylene, A compound according to claim 25.   27. The compound of claim 26, wherein Y is a bond or methylene. (I), the independently ^{R 1} and ^{R 2} are each selected from _hydrogen, C 1 -C ₆ straight or branched chain alkyl and _C 3 -C consisting ₆ alkyl group, as claimed in claim 24 Compound. (I), the independently ^{R 1} and ^{R 2} are each selected from _hydrogen, C 1 -C ₃ straight or branched chain alkyl and _C 3 -C consisting ₆ alkyl group, as claimed in claim 28 Compound. In (ii), one of R ¹ or R ² is aryl or heteroaryl, and the other of the remaining R ¹ or R ² is hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl. 25. A compound according to claim 24. In (iii) a 5- or 6-membered heterocycle in which R ¹ and R ² together with the nitrogen atom to which they are attached contain 1 or 2 heteroatoms selected from the group consisting of N, O and S Alternatively, it forms an 8- to 11-membered bicyclic heterocycle, and the heterocycle and the bicyclic heterocycle may be substituted with 2 or less substituents selected from the group consisting of oxo and halo. 25. A compound according to claim 24. The ring is morpholine, piperidine, piperazine, pyrrolidine, 1,3-thiazolidine, 1H-imidazole, 4,5-dihydro-1H-imidazole, 2,3-dihydroindole, 1,2,3,4-tetrahydroquinoline or At least one substitution selected from the group consisting of 1,2,3,4-tetrahydroisoquinoline, wherein said heterocycle is selected from the group consisting of phenyl, C ₁ -C ₃ alkyl, hydroxy, alkoxy, oxo and halo 32. The compound of claim 31, which is optionally substituted with 1 to 4 groups. In (iv), Y _is a C 1 -C ₆ alkylene, linked to ^{R 2} to form a 3- to 7-membered ring compound of claim 24. The _{3- to} 7-membered ring may be substituted with 1 to 4 at least one substituent selected from the group consisting of phenyl, C ₁ -C ₃ alkyl, hydroxy, alkoxy, oxo and halo. 34. The compound of claim 33, which is a -7 membered ring. The compound is
6- (4-chlorophenyl) -3- [2- (dimethylamino) -1-methyl-1H-benzimidazol-6-yl] thieno [3,2-d] pyrimidin-4 (3H) -one; 25. A compound according to claim 24. Aniline of formula (II) in a solvent with heating:

And a compound of formula (III):

A process for preparing a compound according to claim 1 comprising reacting
[Where:

, R ⁵ , R ⁴ , R ³ , R ² , R ¹ , Ar, Y, Q ¹ , Q ² , Q ³ , q, r, s and t are defined as in formula (I) and R _is a C 1 -C ₄ alkyl] An amino acid of formula (IV) in the presence of at least one coupling agent in a solvent:

And an aniline of formula (II):

And a compound of formula (V):

And cyclizing said compound of formula (V) to produce a compound of formula (I).
[Where:

, R ⁵ , R ⁴ , R ³ , R ² , R ¹ , Ar, Y, Q ¹ , Q ² , Q ³ , q, r, s and t are defined as in formula (I)] Compound of formula (Va):

And a boronic acid and a palladium catalyst using a Suzuki coupling reaction, or an organostannane reagent and a palladium catalyst using a Stille coupling reaction. How to prepare.
[Where:

, R ⁵ , R ⁴ , R ³ , R ² , R ¹ , Ar, Y, Q ¹ , Q ² , Q ³ , q, r, s and t are defined as in formula (I) and T Is a leaving group] Amino ester of formula (III) in the presence of trimethylaluminum in a solvent:

And an aniline of formula (II):

And a compound of formula (Vb):

And the compound of formula (Vb) is cyclized to produce a compound of formula (I).
[Where:

, R ⁵ , R ⁴ , R ³ , R ² , R ¹ , Ar, Y, Q ¹ , Q ² , Q ³ , q, r, s and t are defined as in formula (I)] In the presence of a solvent, a sulfur-containing compound of formula (VI):

And comprising reacting a Raney nickel reducing agent, a method of R ⁵ to prepare a compound of Claim 1 is hydrogen.
[Where:

, R ⁵ , R ⁴ , R ³ , R ² , R ¹ , Ar, Y, Q ¹ , Q ² , Q ³ , q, r, s and t are defined as in formula (I)] Amines of formula (VII):
H-NR ¹ R ² (VII)
An alkylating agent of formula (VIII):

A process for preparing a compound according to claim 1 comprising alkylating with
[Wherein T is a leaving group,

, R ⁵ , R ⁴ , R ³ , R ² , R ¹ , Ar, Y, Q ¹ , Q ² , Q ³ , q, r, s and t are defined as in formula (I)] Amines of formula (VII):
H-NR ¹ R ² (VII)
Is treated with a strong base such as sodium hexamethyldisilazane and the ester of formula (III) in a solvent such as tetrahydrofuran:

And a compound of formula (Vb):

And cyclizing said compound of formula (Vb) to produce a compound of formula (I).
[Where:

, R ⁵ , R ⁴ , R ³ , R ² , R ¹ , Ar, Y, Q ¹ , Q ² , Q ³ , q, r, s and t are defined as in formula (I)]   A method for treating obesity, diabetes, depression or anxiety in a mammal comprising administering to the mammal an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. how to.   44. The method of claim 43, wherein the mammal is a human.   Obesity, diabetes in a mammal, comprising administering to the mammal an effective amount of a pharmaceutical composition comprising the compound of claim 1, a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. How to treat depression or anxiety.   46. The method of claim 45, wherein the mammal is a human.   The compound according to claim 1, in a form combined with at least one selected from the group consisting of an agent for treating diabetes, an agent for treating hypertension and an agent for treating arteriosclerosis, and a salt thereof , Solvates or physiologically functional derivatives.   (I) human ciliary neurotrophic factor, (ii) CB-1 antagonist or inverse agonist, (iii) neurotransmitter reuptake inhibitor, (iv) lipase inhibitor, (v) MC4R agonist, (vi) 5 -The compound of claim 1 in combination with a chemical species for treating obesity selected from the group consisting of an HT2c agonist and (vii) a ghrelin receptor agonist or antagonist, salt thereof, solvent thereof Japanese or physiologically functional derivatives.   A pharmaceutical composition comprising the compound of claim 1 and at least one excipient or carrier.   Use of a compound according to claim 1 for the manufacture of a medicament for treating a condition selected from the group consisting of obesity, diabetes, depression and anxiety in a mammal, preferably a human.